DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 3, 2026 has been entered.
Claims 2-5 and 16 have been canceled.
Claims 1, 6, and 12 have been amended.
Claims 1 and 6-15 are pending in the instant application.
Claims 6-15 stand withdrawn from consideration as being drawn to a nonelected invention. See 37 CFR 1.142(b) and MPEP § 821.03, for reasons of record set forth in the restriction requirement mailed October 6, 2022.
Claim 1 is under examination in this office action as it reads on using antibodies to sort stem cells.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The rejection of claim 1 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement has been withdrawn in view of applicant’s claim amendments received August 3, 2026.
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 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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Miharada et al. (of record) in view of Thiel et al. (of record) and in view of Lee et al.
Miharada et al. disclose isolating a subset of hematopoietic stem cells (HSC) that express GRP78 (see entire document, particularly the abstract and the right column of page 331). HSC were first isolated using magnetic bead sorting followed by staining with anti-GRP78 and fluorescent cell sorting (see particularly the left column of page 342 as well as Figure 2). GRP78+ HSC were found to be competent for repopulating the bone marrow of irradiated mice, with only the GRP78+ HSC being able to do so after 2 weeks in culture (see particularly page 333 as well as the right column of page 342 and Figure 2D). It should be pointed out that HSC are a type of “adult stem cells” (see applicant’s exemplification of the term on page 6 of the instant specification). These teachings differ from the present claimed invention in that even though Miharada et al. isolate HSC using magnetic bead sorting and use anti-GRP78 antibodies as part of the isolation process, the anti-GRP78 antibodies are not disclosed as being attached to the magnetic beads.
Thiel et al. disclose that magnetic cell sorting allows for high sensitivity, high purity, and is useful or isolating rare cells from heterogenous populations (see entire document, particularly the abstract). Magnetic sorting using more than one marker is also disclosed, with such protocols offering the advantages of isolating extremely rare subsets of cells (see particularly Figure 3 as well as section 6, Multiparameter high gradient magnetic cell sorting). Note that magnetic cell sorting, unlike FACS, does not expose the cells to strong mechanical forces that can compromise the viability of recovered cells (see particularly section 4 on page 91).
Lee et al. disclose that mesenchymal stems cells (MSC) are ideal materials for stem cell based therapy and that such cells are located on hypoxic areas of the body (see entire document, particularly the title, abstract, and introduction). They disclose that such cells express GRP78, that the number of MSC expressing GRP78 can be enhanced by exposure to hypoxic conditions for 12 hours, and that such hypoxic conditioning facilities survival and proliferation of transplanted MSC in an in vivo mouse model and that addition of a blocking anti-GRP78 antibody diminishes the efficacy of MSC thus treated (see particularly the results section and Figures 1-6, notably Figures 1C, 4A-D, 6B, and 6D). Indeed, they teach that “hypoxic preconditioning promotes MSC proliferation and migration through elevated GRP78 expression” (see particularly the discussion section).
Therefore it would have been obvious to a person of ordinary skill in the art at the time of the invention that anti-GFP78 antibodies could be joined to magnetic beads as part of a stem cell isolation protocol. Artisans would be motivated to do so as anti-GRP78 antibodies were already used in isolating stem cells using FACS, and switching to magnetic beads offers the advantages of increased expected viability of the recovered cells as compared to FACS as taught by Thiel et al. It should be appreciated that cells which are not present in the recovered anti-GFP78 positive pool express surface GRP78 at levels low enough so as to avoid recovery, and thus separation between surface GRP78 positive and GRP78 negative cells has been achieved. Further, artisans would have been motivated to use MSC rather than HSC when performing such stem cell isolation procedures because MSC are ideal materials for stem cell based therapy that show that GRP78 expression is strongly correlated with proliferation and survival of transplanted MSC in an in vivo mouse ischemia model system as taught by Lee et al.
Applicant's arguments filed August 3, 2026 have been fully considered but they are not persuasive. Applicant argues that Miharada et al. discuss HSC rather than MSC, and that it would have been surprising to artisans that MSC expressing GRP78 would display superior proliferation and survival properties. To support such unexpected proliferation applicant cites data from a post filing non-patent literature document by Choi et al. Applicant also argues that GRP78 expression in MSC is dependent upon passage number, and that this fact is not disclosed by the cited art.
These arguments have been considered but are not persuasive. As discussed in the rejection above, Lee et al. demonstrated that MSC expressing GFP78 had superior proliferation and survival including as part of an in vivo transplantation experiment in mice. Thus applicant’s assertions about GRP78 expression being unexpected correlated with increased proliferative capacity does not appear to be correct as such data was already known to artisans via the disclosure of Lee et al. Further, as recited in claim 1, the active method steps simply sort MSC via magnetic bead separation based only upon if the MSC do or do not express cel surface GRP78. Thus, there is no need for artisans to know or even care about how GRP78 expression is or is not correlated with passage number as all the claimed method’s practitioner need know is does the cell express GRP78, yes or no? With regard to applicant’s allegations that the instant claimed method is actually a method of “overcoming culture induced senescence” and that such a reason is not set forth in the art of either Miharada et al. or Thiel et al., the instant claimed method does not actually “overcome” senescence such as by stopping cells from becoming senescent, but simply sorts for ones that have high GRP78 expression. As taught by Lee et al. it was known that MSC typically inhabit hypoxic cellular environments in vivo, that hypoxic cell culture conditions increased expression of GRP78 (see again most particularly Figure 1C) and that hypoxia treated MSC (i.e. ones that have increased GRP78 expression) survive and are more effective when used for in vivo transplantation studies (see particularly figures 4-6). Thus, contrary to applicant’s assertions the correlation between MSC expression of GRP78 and proliferative capacity was already known in the prior art as disclosed by Lee et al.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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