DETAILED ACTION
This action is in reply to papers filed 6/8/2026. 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 .
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.
Withdrawn Rejection(s)
The 35 U.S.C. 103 rejection of claims 11, 16-23 and 27-28 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.) is withdrawn in view of amendments made to claim 1.
Rejections Necessitated by Amendments
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claim 11, 16-23 and 27-28 are newly are rejected under 35 U.S.C. 103 as being unpatentable over Dezawa et al (PgPub US20110070647 A1, Publication Date 3/24/2011, previously cited) and Honmou et al. (PgPub US20060210544A1, Published 9/21/2006, previously cited).
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 (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).
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. At the time of 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, the ordinary artisan would have administered the Muse cells 3 hours after the onset of cerebral infarction because Honmou teaches infarct size gradually increased when the therapeutic cells after 3 hours.
Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the claimed invention, as a whole, was clearly prima facie obvious.
Applicant’s Arguments/ Response to Arguments
Applicant argues: Dezawa, while disclosing generally the use of Muse cells for treatment of diseases or conditions, Dezawa 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.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Para. 134 of Dezawa is copied below.
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Critically, in the middle of the paragraph, Dezawa teaches “….the pluripotent stem cells or the pluripotent stem cell fractions of the present invention can be used for treatment of diseases due to tissue degeneration or dysfunction. In this case, for example, the pluripotent stem cells or the pluripotent stem cell fractions of the present invention are enriched ex vivo, grown, or caused to differentiate and then returned into the body. For example, the pluripotent stem cells are caused to differentiate into specific tissue cells and then the cells are transplanted into tissue to be treated. Also, in situ cell therapy can be performed by transplantation of such cells. In this case, examples of target cells include hepatic cells, neural cells such as neuronal cells or glial cells, skin cells, and muscle cells such as skeletal muscle cells. The pluripotent stem cells of the present invention are caused to differentiate into these cells, the differentiated cells are transplanted, and then treatment can be performed in situ. Through such treatment, Parkinson's disease, brain infarction, spinal cord injury, myodystrophy, and the like can be treated, for example.
Applicant argues: Because Dezawa only contemplates transplanting pre-differentiated tissue or cells, it lacks an enabling disclosure for and actively teaches away from-administering raw, undifferentiated pluripotent cells directly to a stroke victim with a reasonable expectation of success.
In Response:: Applicant’s arguments have been fully considered, but are not found persuasive. Notably, in para. 134, Dezawa teaches “,,,the pluripotent stem cells or the pluripotent stem cell fractions of the present invention are enriched ex vivo, grown, or caused to differentiate and then returned into the body.” Note Dezawa’s use of the term ‘or’. It is further noted that at para. 136, Dezawa explicitly teaches “…when the pluripotent stem cells or the pluripotent stem cell fractions of the present invention are used for treatment, their differentiation may be caused ex vivo, in vivo, or in vitro.” Also note that the claims are not drawn to administering undifferentiated pluripotent cells directly to a stroke victim.
Applicant argues: Working examples provided in Dezawa describe the transplantation of Muse cells into immunodeficient mice testis for teratoma formation (e.g., [0l82]-[1083]) or into general damaged tissues (e.g., muscle, liver, skin). The in vivo experiments are carried out in immunodeficient mouse models specifically using NOG or SCID mice. See Dezawa, P [0170]. These mice models lack functional T, B, and NK cell responses.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Per MPEP 2123, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Applicant argues: Honmou administered 1 x 106 to 1 x 107 MSCs to rats and observed only modest functional improvement (See Honmou Figs. 8 and 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 Published Application, Fig. 1). There is no teaching or motivation in Honmou (or Dezawa) to select Muse cells from among the heterogeneous MSC population for the treatment of cerebral infarction, nor any reasonable basis for predicting that such selection would yield the unexpectedly superior results demonstrated here.
In Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues: Further, the Office Action does not identify any express or implicit teaching, suggestion, or reasonable expectation of success that would motivate an artisan to select for Muse cells, to administer them using the claimed dosing regimens, or to evaluate success using the newly recited, objective clinical criteria. The mere fact that both references relate to stem cells does not provide an adequate reason to combine them, especially where the references disclose fundamentally different cell populations, isolation methods, and therapeutic contexts.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Note that both references do not merely relate to “stem cells”. Indeed, both references are drawn to CD105+ cells derived from mesenchymal tissue and used for treating cerebral infarctions.
Applicant argues: The present application demonstrates that Muse cells provide robust and long-lasting recovery in a rat model of cerebral infarction at doses (1 x 104 cells) far lower than those required for general MSCs (1 x 106 - 1 x 107 cells), as shown in Figs. 1, 2, and 5 of the present application and in the Uchida et al. reference (Uchida et al., STEM CELLS 2016;34:160-173 1). In contrast, the same dose of non-Muse MSCs yields no effect, confirming that Muse cells are a unique, nonobvious, and superior cell type for this indication.
In Response:. Insofar as Dezawa teaches MUSE cells, arguments drawn to the unexpected results of MUSE cells are not found persuasive.
Applicant argues: Furthermore, claim 11 explicitly recites an active "determining" step which defines a new, objective, and durable clinical endpoint for evaluating the success of Muse cell therapy in stroke.
In Response: Claim 11 is copied below. There is no step of ‘determining’ recited in claim 11.
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Applicant argues: Applicant additionally notes that the examiner's rationale for combining Dezawa and Honmou is based on impermissible hindsight. The Office Action appears to use knowledge of Applicant's invention-specifically, the use of SSEA-3-positive Muse cells, their precise dosing, and the novel, objective criteria for clinical success-to reconstruct the claimed invention from references that, individually or collectively, lack any teaching or suggestion of these elements.
In Response: 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).
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.
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 extension fee 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 date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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