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 .
Applicant’s response and amendments received March 3, 2026 are acknowledged.
Claims 2-5 and 16 have been canceled.
Claims 1 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Claims 6-15 stand withdrawn from consideration as being drawn to a nonelected invention.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.
Claim 1 is rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has claimed a method of selectively isolating young adult stem cells which express GRP78 in their plasma membrane from old stem cells that express no GRP78 on the cell surface and older stem cells. The process steps recited as achieving this goal rely upon the binding of an anti-GRP78 antibody to cell surface expressed GRP78, capturing such antibody labeled cells with secondary antibody coated magnetic beads, followed by exposure to a magnetic field to physically separate the magnetic beads (and any cells attached thereto) from the rest of the cell culture milieu. Thus the process step is a binary operation separating those cells that express GRP78 on their cell surface from cells which do not express GRP78 on the surface. This is because antibodies are large molecules that cannot gain access to the interior of a cell unless the cell has been fixed and permeabilized (and therefore dead). As such the assay as currently can only determine if GRP78 is or is not cell surface expressed and provides no information concerning other locations in a cell where it may be expressed or if it is even is expressed. As presently recited the claim preamble states that young stem cells are separated from “old stem cells expressing no GFP78 in the membrane” and from “older stem cell passages”. Notably, while “old” stem cells are recites as not expressing GRP78 in the membrane, the claim does not recite any feature which necessarily identifies a stem cells as “older”. In other words, three cell populations are recited (i.e. young, old, and older) yet the recited assay is binary in that the cell either does or does not express GRP78 in the membrane. How can an assay that provides a yes/no answer split a population into three cell types? Even if it is assumed for the sake of argument that “old” and “older” both do not express GRP78 in the plasma membrane, how is the practitioner of the claimed method to discriminate between “old” and “older” cells? If such a discrimination isn’t possible in the assay as recited, why are both populations recited as the artisan practicing the method as claimed does not appear to be able to tell if cells that are GRP78 are “old”, “older” or a mixture of “old and older” cells. As has been discussed repeatedly throughout prosecution, while the specification asserts that GRP78 protein is expressed only at the nucleus position in the “oldest” cells, data concerning subcellular localization of GRP78 is not collected as part of the instant claimed assay and note that the recitation that the stem cells are “adult stem cells” does not reasonably say anything about subcellular localization of any given marker. It should be noted that in the specification, working examples 5 and 7 killed cells such that intracellular localization could be collected whereas working example 8 using MACS separation explicitly teaches “This can be used to specifically screen only cells in which the GRP78 protein is present in the membrane.” Thus applicant’s own working examples indicate that the presently claimed assay can only tell if a cell does or does not express GRP78 on its cell surface and can say nothing about where else it may or may not be expressed such as the cell nucleus. Thus if the working example teaches that only two populations can be identified, i.e. those expressing GRP&8 on the cell surface and those lacking expression of GRP78 on the cell surface, why does claim 1 recite 3 cell populations as discussed above (i.e. young, older, older)?
Amending the claim to recite a separation between only two populations, i.e. those cells that express GRP78 on their membrane and cells that do not express GRP78 on their cell membrane, is likely to obviate the issued raised above.
Applicant's arguments filed March 3, 2026 have been fully considered but they are not persuasive. Applicant argues that the phrase “where GRP78 protein is expressed only in the nucleus position” was deleted and that the claim now recites only two cell populations, those that express GRP78 on the plasma membrane and are bound by the antibody and those that do not express GRP78 on the plasma membrane. However, as discussed above the claim identifies three types of cells, that is “young”, “old” and “older”, yet using a single surface marker sorting into more than two populations (i.e. expressing or not expressing) is not reasonably possible. The rejection is maintained.
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)
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).
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. It should also be noted that GRP78 expression was the only marker that served to distinguish between HSC that readily did or did not serve to reconstitute the bone marrow in a transplantation setting after the cells had been cultured for 2 weeks (see in particular figure 2D of Miharada et al.). Given that cells administered as part of BMT are regularly cultured in order to expand them to sufficient number for use in transplantation, artisans would be motived to identify HSC based only on GRP78 expression, and use only those expressing GRP78, as those are the only cells capable of engraftment post-culturing as per the teachings of Miharada et al.
Applicant's arguments filed March 3, 2026 have been fully considered but they are not persuasive. Applicant begins by arguing that they believe that assertions about where GRP78 resides, other than the plasma membrane which is measured by the claimed assay, are important for patentability even though data demonstrating where else GRP78 may or may not be located are not collected as part of the claimed assay protocol. Applicant then proceeds to reproduce a figure from a scientific publication demonstrating that in fixed and permeabilized cells (i.e. dead cells) GRP78 is also found in the cytoplasm of cells that have surface GRP78 while cells without surface GRP78 have intracellular GRP78 located mostly near the nucleus. Applicant asserts that this means that GRP78 surface expression necessarily acts as a proxy marker for intracellular distribution. Applicant argues this intracellular localization data was not known in the prior art and therefore “the remarkable effect of this novel method cannot be easily predicted by a person skilled in the art by combining the cited references. Specifically, the present invention is not simply a combination of existing technologies, but an innovative stem cell selection method that utilizes the functional differences of GRP78 depending on the intracellular location. In particular, the identification of young stem cells through cell membrane-specific GRP78 expression has not been reported in the prior art. Thus, the inventiveness of the present invention should be acknowledged.”
These arguments have been considered and are not persuasive. As discussed in the enablement rejection as well as in prior office actions earlier in the prosecution history, the claimed magnetic cel separating assay can only determine if a given cell does or does not express upon its cell surface a particular antigen determinant, in the instant case that determinant is GRP78. As discussed in the rejection, Miharada et al. sorted stem cells using GRP78 surface expression and artisans would have been motivated to modify such methods to use magnetic bead separation as such techniques are gentler to cells as taught by Thiel et al. As evidenced by applicant’s own data, only young stem cells express GRP78 on their plasma membrane. Thus, any stem cell which expresses GRP78 on the cell surface must be “new” even if artisans would not know how “new” such a cell was as compared to cells which lack GRP78 surface expression. Thus, assertions about where GRP78 resides, such as being in the nucleus, are inappropriate as a) there is no active method step wherein such data is collected (perhaps unsurprising as collecting such data reasonably would require permeabilization resulting in cell death) and b) a better scientific explanation for how or why the art works does not restore patentability. For example, aspirin/acetylsalicylic acid was long known in the art to be useful for treating headaches and pain long before its mechanism of action by irreversibly inactivating cyclooxygenases was discovered, but such scientific knowledge when gained did not make aspirin, or methods of administering it to treat headache, patentable again. Applicant is remined that something which is old does not become patentable upon the discovery of a new property. Indeed, as set forth in MPEP 2112, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In the instant case, as evidenced by Miharada et al., it has been long known in the art that GRP78 is a marker for stem cells. Thus, applicant’s discussion of GRP78 expression patterns changing over time provide a better and more complete scientific explanation for why GRP78 is a good marker for stem cells, but the fact remains that GRP78 was known in the prior art to be a surface-expressed marker for stem cells before the filing of the instant application. Given that mind reading devices are not (yet) available, the “why” of a method reasonably is a mental process that does not add patentable distinctiveness as compared to the observable “what” of the physical process steps, and as set forth in the rejection of record artisans would have been motivated to sort stem cells magnetically using GRP78 as a cell surface marker protein. The rejection is maintained.
No claims are allowable.
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.
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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