DETAILED ACTION
This action is in reply to papers filed 12/24/2025. Claims 11, 16-23 and 27-28 are pending and examined herein.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/24/2025 has been entered.
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20210213068A1, Published 3/31/2021.
Maintained Rejection(s)
Claim(s) 11, 16-23 and 27-28 remain ejected under 35 U.S.C. 103 as being unpatentable over Dezawa et al (PgPub US20110070647 A1, Publication Date 3/24/2011), Honmou et al. (PgPub US20060210544A1, Published 9/21/2006; Ref. 4 in IDS filed 9/8/2021) and Thau-Zuchman et al. (J Neurotrauma. 2012 Jan 20;29(2):375-84.). Applicant’s arguments will be addressed following maintained rejection.
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.
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.
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(s) 11, 16-23 and 27-28 remain rejected under 35 U.S.C. 103 as being unpatentable over Dezawa et al (PgPub US20110070647 A1, Publication Date 3/24/2011; Ref. 3 in IDS filed 9/8/2021) Honmou et al. (PgPub US20060210544A1, Published 9/21/2006; Ref. 4 in IDS filed 9/8/2021) and Thau-Zuchman et al. (J Neurotrauma. 2012 Jan 20;29(2):375-84.). Although maintained, the rejection has been updated to reflect amendments to claim 11.
Regarding claim 11 (in-part), Dezawa et al. teaches treating a brain infraction (Pg. 11, para. 134, five lines from bottom of paragraph) in a human (Pg. 11, para. 134;Pg. 12,para. 142) with a therapeutically effective dose (Pg. 5, para. 75; Pg. 12, Col. 2, ‘Example 1’; Pg. 12, para. 142) of pluripotent stem cells positive for SSEA-3 and isolated from human (Pg. 17-18, para. 206-208) mesenchymal tissue or cultured mesenchymal cells (see Dezawa, claim 1 and claim 14). Regarding step (i), Dezawa et al. teach the pluripotent stem cells are CD105-positive (see Dezawa, claim 2). Regarding step (ii), Dezawa et al. teach the pluripotent stem cells have low or absent telomerase activity (see Dezawa, claim 6). Regarding step (iii), Dezawa et al. teach the pluripotent stem cells have ability to differentiate into any of the three germ layers (see Dezawa, claim 7).Regarding step (iv), Dezawa et al. teach the pluripotent stem cells have an absence of demonstration of neoplastic proliferation (see Dezawa, claim 8). Regarding step (iv), Dezawa et al. teach the pluripotent stem cells self-renewal ability (see Dezawa, claim 9).
Further, Examiner notes that although Dezawa does not ipsis verbis teach treating a ‘cerebral infraction’, the disclosure of treating a ‘brain infarction’ by Dezawa is reasonably considered equivalent to treating a ‘cerebral infraction’ as para. 30 of the instant PgPub teaches a form of cerebral infarction to be an “acute brain infarction”.
Regarding claim 16, Dezawa et al. teach the pluripotent stem cells positive for SSEA-3 contain a concentrated cell fraction as a result of stimulation by external stress (see Dezawa, claim 17 and claim 18).
Regarding claim 17, Dezawa et al. teach the pluripotent stem cells positive for SSEA-3 have been separated by using the positiveness of SSEA-3 as an index (Pg. 8, para. 103).
Regarding claim 18, Dezawa et al. teach the pluripotent stem cells are CD117-negative and CD146-negative (see Dezawa, claim 3).
Regarding claim 19, Dezawa et al. teach the pluripotent stem cells are CD117-negative, CD146-negative, NG2- negative, CD34-negative, vWF-negative and CD271-negative (see Dezawa, claim 4).
Regarding claim 20, Dezawa et al. teach the pluripotent stem cells are CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snail-negative, Slug-negative, Tyrpl-negative and Dct-negative (see Dezawa, claim 5).
Regarding claim 21, Dezawa et al. teach the pluripotent stem cells have the ability to differentiate into nerve cells (Pg. 2, para. 21).
With further regards to claim 11 and with regards to claims 22 and 23, Examiner notes that although Dezawa does not specifically teach (1) administering the pluripotent stem cells positive for SSEA-3 improves motor function of the human, (2) administering the pluripotent stem cells positive for SSEA-3 reduce infarct size by a mechanism involving regeneration of brain tissue or that (3) the pluripotent stem cells positive for SSEA-3 improves or restores a brain dysfunction due to cerebral infarction by a mechanism involving regeneration of brain tissue, these results are inherent to method taught by Dezawa because the method steps and/or the pluripotent stem cells (in and of themselves) are taught by Dezawa are identical to those claimed (emphasis added).
As is established by case law, the author does not need to recognize an effect if the effect is inherent. Indeed, the discovery of a new use for an old structure based on unknown properties of the structure might be patentable to the discoverer as a process of using. In re Hack, 245 F.2d 246, 248, 114 USPQ 161, 163 (CCPA 1957). However, when the claim recites using an old composition or structure and the "use" is directed to a result or property of that composition or structure, then the claim is anticipated. In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966). See M.P.E.P. § 2112.02.
Therefore, because the step of administering to a subject in need thereof, pluripotent stem cells positive for SSEA-3 isolated from human (Pg. 17-18, para. 206-208) biological mesenchymal tissue or cultured mesenchymal cells, is taught by Dezawa, Dezawa anticipates the effect(s) of said step of administering. That is, Dezawa inherently teaches (1) the reduction in infarct size by a mechanism involving regeneration of brain tissue, (2) improves or restores a brain dysfunction due to cerebral infarction by a mechanism involving regeneration of brain tissue and (3) improves or restores a brain dysfunction due to cerebral infarction by a mechanism involving regeneration of brain tissue.
And although Dezawa teaches a therapeutically effective dose (Pg. 12, para. 142) can be appropriately determined depending on an organ to be regenerated, a tissue type, or a size (Pg. 10, para. 131), Dezawa fails to teach the pluripotent stem cells are administered as a therapeutically effective dose per a human: (a) 1 to 1.5 x 105 cells/kg per a human based on body weight; (b) 1 to 10 times at 1 x 103 cells to 2 x 107 cells per a human; or ( c) total individual doses of 1 x 103 cells to 2 x 108 cells, 1 x 104 cells to 1 x 108 cells, 2 x 104 cells to 5 x 107 cells, or 5 x 104 cells to 2 x 107 cells (as further in claim 11) and that the pluripotent stem cells positive for SSEA-3 are administered to cerebral parenchyma (claim 28), and the pluripotent stem cells accumulate in a region bordering the infarction and differentiate into nerve cells (as further in claim 11). Additionally, Dezawa fails to teach the administration of the pluripotent stem cells positive for SSEA-3 are administered within 3 to 48 hours of infarction onset (as in claim 27).
Before the effective filing date of the claimed invention, Honmou et al. taught successful treatment of a cerebral infarction by administering 1×104 CD105+ mesenchymal cells (as further in claim 11) (Pg. 32, para. 502). Note that Honmou specifically teaches an intracerebral transplantation (as in claim 28) (Pg. 24, para. 362+) and that the CD105+ mesenchymal cells migrate to the cerebral infarction site (brain parenchyma) and differentiate into nerve cells (Pg. 19, para. 280, Pg. 38, para. 584; Pg. 5, para. 45) (as further in claim 11). Honmou discloses the cells are administered within 6 hours of infarction onset (as in claim 27) (Pg. 13, para. 170).
However, neither Dezawa et al. nor Honmou et al. teach evaluating bran dysfunction using the Neurological Severity Score (NSS) for at least three months after administration (as further in claim 11).
Before the effective filing date of the claimed invention, Mahmood et al. investigated the effects of human bone marrow stromal cell (hMSC) administration in rats for 3 months after traumatic brain injury (TBI) (Abstract). Mahmood teaches recovery began in the second week and persisted at all subsequent evaluation times in both PBS-treated and MSC-treated groups. Motor function tested by the NSS recovered faster than sensory and beam-balance functions. From 8 to 12 weeks after injury, residual deficit scores were present primarily on the beam-balance and sensory tests of the NSS. NSSs for all the hMSC-treated groups were significantly lower than the NSSs of the PBS-treated groups, indicating an improvement in the functional outcome (Fig. 3). The treated animals showed this improvement uniformly, with little variation among them, and this improvement was seen as early as 14 days after TBI and was still evident at Day 84 (paragraph bridging Pg. 1028-1029). Thus establishing long-term
functional improvement persists over time (Pg. 1026, Col. 2, para. 1).
The combination of prior art cited above in all rejections under 35 U.S.C.103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1,148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 389, 82 USPQ2d 1385 (2007): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention."
In the present situation, rationale G is applicable. Before the effective filing date of the claimed invention, it would have been prima facie obvious to an artisan of ordinary skill to combine the teachings of Dezawa et al., wherein Dezawa teaches administering a therapeutically effective dose of CD105+ mesenchymal tissue derived cells for the purposes of treating a cerebral infarction, with the teachings of Honmou et al., wherein Honmou teaches administration of 1×104 cells CD105+ mesenchymal cells to a subject having a cerebral infarction was therapeutically effective in treating the cerebral infarction.
That is, a person of skill in the art would have found it prima facie obvious to administer at least 1×104 cells of Dezawa to a patient having cerebral infarction because Honmou teaches this dosage is therapeutically effective. Moreover, one of ordinary skill in the art would have found it prima facie obvious to therapeutic efficacy of the administered MSCs by evaluating NSS for at least 3 months, in order to establish that therapeutic efficacy persisted over time.
Thus, the modification would have been prima face obvious.
Applicant’s Arguments/Response to Arguments
Applicant argues: Applicant argues that Dezawa at para. 134 and 142 describes pluripotent stem cells and their general therapeutic use. However, the reference does not specifically disclose the direct administration of Muse cells for treatment of cerebral infarction in humans, nor does it provide a working example, method, or reasonable expectation of success for such an application/administration. However, in this recitation [para. 142 of Dezawa], "cerebral infarction" is not even listed as an example of a treatable disease. As such, in view of the disclosure of Dezawa et al., a person of ordinary skill in the art would have no expectation of success of being able treat a cerebral infarction in a human in need thereof by administering a therapeutically effective dose of pluripotent stem cells. dose ... ") is insufficient to provide a reasonable expectation of success for the specific method claimed (See, [0142]).
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Critically, Dezawa fails to list any specific disease in para. 142, see below.
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Thus, in view of para. 142, one of ordinary skill in the art would have a reasonable expectation that any disease identified in Dezawa could be treated by the method of administering as set forth in Dezawa. Note that obviousness does not require absolute predictability, only a reasonable expectation of success (see MPEP 2144).
Applicant argues: Applicant respectfully disagrees with the Examiner's response to Applicant's prior arguments, specifically those found in paragraphs 10 and 11 on pages 5-6 of the Final Office Action. In particular, the Examiner's reliance on Dezawa paragraph [0142] is misplaced, as that section of Dezawa does not identify or describe any specific diseases as being amenable to treatment with Muse cells. The Examiner's rationale appears to be premised on the assumption that, in view of Dezawa [0142], a person of ordinary skill in the art would have had a reasonable expectation that Muse cells and their administration methods could be successfully applied to treat any disease. Applicant submits that this interpretation overextends the actual teachings of Dezawa and is not supported by the cited disclosure. While paragraph [0142] may generically refer to the therapeutic use of Muse cells, it provides no basis for a reasonable expectation of success in treating cerebral infarction or any specific condition. As a matter of scientific fact, only embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells) have been shown to possess the capacity to differentiate into any cell type, but these differ fundamentally from Muse cells as claimed, particularly in their tendency toward teratoma formation. Muse cells, by contrast, as recited in the present claims, exhibit an absence of neoplastic proliferation and do not exhibit tumorigenic behavior. Accordingly, a person of ordinary skill in the art, reviewing Dezawa [0142]-which contains no mention of any particular disease-would not reasonably expect Muse cells to be effective for any and all diseases. It follows that the cited art does not support a reasonable expectation of efficacy for the specific treatment of cerebral infarction, as now claimed.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. At the outset, it must be noted that contrary to Applicant’s suggestion, Examiner did not state that any disease can be treated by MUSE cells(~The Examiner's rationale appears to be premised on the assumption that, in view of Dezawa [0142], a person of ordinary skill in the art would have had a reasonable expectation that Muse cells and their administration methods could be successfully applied to treat any disease.). As Examiner previously noted, and as noted above, Examiner concluded that one of ordinary skill in the art would have a reasonable expectation that any disease identified in Dezawa could be treated by the method of administering as set forth in Dezawa. Para. 134, previously cited in ‘Response to arguments’ identifies ‘brain infarction’ as a disease to be treated by MUSE cells. See below.
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When read in context, it is clear that Dezawa teaches the pluripotent stem cells or the cells differentiated therefore can be used to treat these identified diseases. In fact, para. 21 teaches such an embodiment.
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In reading this paragraph, one of ordinary skill in the art would know that the pluripotent stem cells of Dezawa are capable of being transplanted for purposes of treatment insofar as they do not undergo neoplastic differentiation.
Applicant argues: Dezawa et al. is devoid of any working example of Muse cell administration for cerebral infarction, let alone in a clinically relevant animal model or human. In the biotechnology field, unpredictability is high, and enablement and reasonable expectation of success require more than a generic statement of utility.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Per MPEP 2121, a prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; “proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation.”
Applicant argues: Honmou et al. does not even mention SSEA-3 (an early embryonic marker).
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Honmou teaches treatment of a cerebral infarction with CD105+ mesenchyme derived cells. The MUSE cells of the instant invention are CD105+ mesenchyme derived cells. Thus, a reasonable expectation of using the dose used to treat the cerebral infarction in Honmou to treat the cerebral infarction of Dezawa is present.
Applicant argues: Honmou administered 1 x 106 to 1 x 107 MSCs to rats and observed only modest functional improvement (See, Figs. 8, 19). In contrast, the present application demonstrates robust and long-lasting recovery in the rat model with as few as 1 x 104 Muse cells, and no such effect is observed with non-Muse MSCs at the same dose (See, Fig. 1).
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Note that the dosage recited in claim 11 is not as limited as the rat model Applicant cites. Thus, Applicant cannot argue an unexpected result with the dosage of the rat model.
Applicant argues: The selection of an evaluation metric does not address the key inventive concepts of the claims: the specific cell population, its properties, and its unexpected efficacy. Mahmood et al. does not cure the deficiencies of the primary references, nor does it provide a teaching or motivation to select Muse cells or predict their efficacy in cerebral infarction models.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Note that Mahmood was cited specifically for teaching using the NSS to evaluate brain dysfunction after three months. Arguments drawn to deficiencies of the Muse cells/Dezawa have been previously addressed.
Applicant argues: Neither Dezawa nor Honmou teach, suggest, or motivate one of ordinary skill to select Muse cells over other stem cells for use in cerebral infarction. Applicant submits that the Examiner's rationale is based on impermissible hindsight. At the time of the invention, the literature included numerous reports on different MSC populations. The selection of Muse cells for this purpose required inventive insight, not mere routine optimization. The alleged rational for obviousness lacks an explanation for why a skilled person would choose Muse cells over the cells disclosed in Honmou. Furthermore, the rational lacks a reason to combine the references in a way that uses the administration of Honmou, which used stem cells entirely different from Muse cells, in lieu of transplantation as taught in Dezawa.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. As has been previously noted, although Dezawa does not ipsis verbis teach treating a ‘cerebral infraction’, the disclosure of treating a ‘brain infarction’ by Dezawa is reasonably considered equivalent to treating a ‘cerebral infraction’ as para. 30 of the instant PgPub teaches a form of cerebral infarction to be an “acute brain infarction”. Honmou teaches treatment of a cerebral infarction with CD105+ mesenchyme derived cells. The MUSE cells of the instant invention are CD105+ mesenchyme derived cells. Thus, a reasonable expectation of using the dose used to treat the cerebral infarction in Honmou to treat the cerebral infarction of Dezawa is present.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
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/TITILAYO MOLOYE/ Primary Examiner, Art Unit 1632