DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/05/2026 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-7 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1, as amended, recites the limitation “the genetic defect.” There is insufficient antecedent basis for this limitation in the claim. It is also what actually constitutes the “genetic defect.” The dependent claims do not add additional clarity and, therefore, are also indefinite. For purposes of compact prosecution and applying prior art, claim 1 was interpreted herein to refer to a genetic defect associated with amyotrophic lateral sclerosis (ALS).
It is noted any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to this rejection. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 112-Scope of Enablement
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.
Claims 1-7 and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating amyotrophic lateral sclerosis (ALS) in mice, does not reasonably provide enablement for treating ALS in any subject. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The instant claims, as amended, are drawn to a method of treating ALS in a subject, the method comprising intravenously administering to the subject, a cell preparation comprising, as an active ingredient, an effective amount of pluripotent stem cells positive for SSEA-3 isolated from mesenchymal tissue of a body or cultured mesenchymal cells.
The level of skill in the art is high and would include, e.g., Ph.D. level scientists.
The exemplary embodiments in the Specification are limited to two ALS animal models, i.e., a mutant SOD1 (G93A) transgenic mouse model (Example 1) and a human transactive response (TAR) DNA binding protein 43 kDa (TDP-43) transgenic mouse model (Example 2), which demonstrate limited therapeutic efficacy for ALS in the mice.
The Specification offers no working examples or reasonable direction to use SSEA-3-postive pluripotent stem cells for treating ALS in virtually any subject, including other rodents, canines, felines, primates, humans, etc.
Vinsant et al. (Brain and Behavior, 3(4):335-350 (2013), prior art of record) evidences that “numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials” (Abstract). More generally, Hobson et al. (Medic. 44(9):552-556 (2016), prior art of record) evidences that MND is a disabling and ultimately fatal disease of the motor system, having a variable, unpredictable prognosis, with few effective treatments in virtually any subject (Abstract; page 554, Giving the diagnosis). Hobson further evidences that riluzole is the only drug licensed for treatment of ALS and only prolongs median survival by approximately 3 months (page 555, Pharmacological treatments). As such, there is little predictability in the art for treating ALS in human, let alone canines, felines, primates, etc.
In view of the foregoing, a vast quantity of experimentation would be needed to use the invention based on the content of the disclosure.
Accordingly, the Specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Claim Rejections - 35 USC § 103
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.
Claims 1-7 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Uccelli et al. (Mol. Med. 18:794-804 (2012), prior art of record, hereinafter “Uccelli”) in view of Dezawa (Cell Transplant., 25:849-861 (2016), prior art of record, hereinafter “Dezawa2”) as evidenced by Dezawa et al (WO 2011007900, prior art of record, hereinafter “Dezawa”).
Regarding claim 1, Uccelli teaches intravenous (IV) administration of mesenchymal stem cells (MSCs) improves survival and motor function in experimental Amyotrophic Lateral Sclerosis (ALS) mouse models (Abstract). The reference does not explicitly teach that the MSCs are pluripotent stem cells positive for SSEA-3 isolated from mesenchymal tissue of a body or cultured mesenchymal cells, as claimed. It is noted that the claimed stem cells are Muse cells (see Abstract; Specification, as published, ¶¶ 0103-0111).
Dezawa2 teaches Muse cells, a subset of MSCs, are able to generate cells representative of all three germ layers from a single cell, and are nontumorigenic and self-renewable (Abstract). Dezawa2 further teaches that “Muse cells are particularly unique compared with other stem cells in that they efficiently migrate and integrate into damaged tissue when supplied into the bloodstream, and spontaneously differentiate into cells compatible with the homing tissue. Such a repairing action of Muse cells via intravenous injection is recognized in various tissues including the brain, liver, and skin” (Abstract). Dezawa2 teaches “Muse cells render induction into the target cell type prior to transplantation unnecessary. They can repair tissues in two simple steps: collection from mesenchymal tissues, such as the bone marrow, and intravenous injection. The impressive regenerative performance of these cells provides a simple, feasible strategy for treating a variety of diseases” (Abstract). Dezawa2 teaches “[f]rom the standpoint of clinical treatment, allogenic cell therapy would be more practical than autologous therapy because autologous therapy would require more time to collect and expand Muse cells for clinical scale and would not be applicable to acute-phase patients” (FIG. 7; page 10, future perspectives).
One of ordinary skill in the art would have been motivated to use donor Muse cells taught by Dezawa2, which would lack ALS genetic defects, in the method taught by Uccelli due to the specific and advantageous properties of Muse cells compared to other MSCs with a reasonable expectation of success.
Moreover, given that Dezawa2 teaches Muse cells and the instant claims are drawn to Muse cells, absent evidence to the contrary, the Muse cells taught by Dezawa2 inherently would have the ability to engraft into the spinal cord and differentiate into astrocyte-lineage cells expressing glial fibrillary protein (GFAP). “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Regarding claim 2, Dezawa2 teaches concentrating the pluripotent stem cells positive for SSEA-3 by external stress treatment, thereby obtaining a cell fraction for IV administration (FIG. 7).
Regarding claim 3, Dezawa2 teaches that the stem cells are CD105-positive (FIG. 2).
Regarding claim 4, as evidenced by Dezawa, Muse cells are CD117-negative and CD146-negative (page 4, [4]).
Regarding claim 5, as evidenced by Dezawa, Muse cells are CD117-negative, CD146-negative, NG2-negative, CD34-negative, vWF-negative, and CD271-negative (page 4, [4]).
Regarding claim 6, as evidenced by Dezawa, Muse cells are CD34-negative, CD117-negative, CD146-negative, CD271-negative, NG2-negative, vWF-negative, Sox10-negative, Snai1-negative, Slug-negative, Tyrp1-negative, and Dct-negative (page 4, [4]-[5]).
Regarding claim 7, as evidenced by Dezawa, Muse cells: i) have low or no telomerase activity (page 4, [6]; ii) have the ability to differentiate into any of three germ layers (page 5, [7]); iii) exhibit non-tumorigenic proliferation (page 5, [8]); and iv) have self-renewal ability (page 5, [9]; see also Dezawa2, Abstract).
Regarding claim 9, given that Dezawa2 teaches Muse cells and the instant claims are drawn to Muse cells, absent evidence to the contrary, the Muse cells taught by Dezawa2 would, protect motor neurons and reduce denervation and muscle fiber atrophy. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments filed 05/05/2026 have been fully considered but they are not persuasive. Applicant’s arguments are discussed to the extent they apply to the current grounds of rejection set forth above.
On pages 5-6 of the Response, Applicant urges that the Specification demonstrates “extensive working examples demonstrating therapeutic efficacy for ALS across two different ALS mouse models.” However, as previously discussed, it was well established that ALS mouse models, including the SOD1 mouse model, do not translate to efficacy in other organisms. As discussed above, Vinsant evidences that “numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials” (Abstract). As such, the evidence of record establishes that the results obtained in the ALS mouse models disclosed by the Specification cannot reasonably be extrapolated to virtually any subject, including primates and humans.
On page 7 of the Response, Applicant urges that Uccelli teaches away from the claimed invention. Applicant urges that Uccelli found that MSCs “scantly home to the central nervous system and poorly engraft,” while amended claim 1 requires engraftment into the spinal cord, and that “Uccelli concluded that the clinical effect of MSCs is ‘not likely to rely on long-term engraftment.’” Applicant further urges that Uccelli teaches that MSCs act through paracrine mechanisms rather than through engraftment and differentiation as required by amended claim 1, and that Uccelli observed no motor neuron protection.
It is well established that 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).
Here, the instant claims are rejected over the combination of Uccelli and Dezawa2—not Uccelli alone. As discussed above, Dezawa2 teaches that Muse cells are particularly unique compared with other stem cells in that they efficiently migrate and integrate into damaged tissue when supplied into the bloodstream, and spontaneously differentiate into cells compatible with the homing tissue. As further discussed above, Dezawa2 teaches that “Muse cells render induction into the target cell type prior to transplantation unnecessary. They can repair tissues in two simple steps: collection from mesenchymal tissues, such as the bone marrow, and intravenous injection.”
As such, the issues alleged by Applicant with respect to Uccelli provide a clear teaching, suggestion, and motivation to replace the MSCs taught by Uccelli with the Muse cells taught by Dezawa2 since Dezawa2 teaches that Muse cells migrate and integrate into damaged tissue when supplied into the bloodstream, and spontaneously differentiate into cells compatible with the homing tissue.
Moreover, engraftment into the spinal cord and differentiation into astrocyte-lineage cells expressing glial fibrillary protein (GFAP) are not method steps to be performed, but, rather, the underlying mechanism of action of Muse cells. The claimed method requires administration of Muse cells to a subject to treat ALS; likewise, Uccelli and Dezawa2 teach administration of Muse cells to a subject to treat ALS. Engraftment and differentiation of the Muse cells would, absent evidence to the contrary, be the inherent result and mechanism of action of the method taught by Uccelli and Dezawa2. Reciting how the claimed method works does not distinguish the method from the prior art of record.
“[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). “Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
On page 9 of the Response, Applicant urges that “Dezawa2 does not teach or suggest that Muse cells have the capacity to engraft into the spinal cord and differentiate into astrocyte-lineage cells expressing GFAP in the context of ALS treatment.” As discussed above, the capacity to engraft and differentiate are not active method steps to be performed, but, rather, how the claim method functions after administration of the Muse cells. A method of administering Muse cells to treat ALS is indistinguishable from a method of administering Muse cells to treat ALS, wherein the Muse cells have the capacity to engraft into the spinal cord and differentiate into astrocyte-lineage cells expressing GFAP, since both methods recite identical steps and achieved the identical result, i.e., treatment of ALS, even if the underlying mechanism of action is not specifically recited.
Moreover, the instant claims require use of Muse cells, which are the same cells taught by Dezawa2. As such, if the Muse cells taught by Dezawa2 do not have the capacity to engraft into the spinal cord and differentiate into astrocyte-lineage cells expressing GFAP, then neither do the instantly claimed Muse cells. “Products of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
On page 10 of the Response, Applicant urges that the Specification demonstrates that the engraftment and differentiation of Muse cells in the spinal cord are unexpected outcomes, i.e., that multiple i.v. administration of Muse cells improved clinical scores in the RotaRod, hanging wire and muscle strength of lower limb in the ALS model G93A Tg mice, and “that MSCs did not engraft or differentiate in the spinal cord, whereas Muse cells did.”
However, as discussed above, the prior art establishes that the results in ALS mouse models would not reasonably translate to efficacy in virtually any subject, as claimed, and the prior art already recognized the superior properties of Muse cells over MSCs, i.e., that Muse cells are particularly unique compared with other stem cells in that they efficiently migrate and integrate into damaged tissue when supplied into the bloodstream, and spontaneously differentiate into cells compatible with the homing tissue.
On page 11 of Response, Applicant urges that the property of Muse cells “after engrafting into the spinal cord, protect motor neurons and reduce denervation and muscle fiber atrophy” were not known to be inherent properties of Muse cells. As Applicant is aware, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003). “[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).
Here, the prior art provides a clear teaching, suggestion, and motivation to substitute the MSCs taught by Uccelli for the Muse cells taught by Dezawa2 because as discussed above, Dezawa2 teaches that “Muse cells are particularly unique compared with other stem cells in that they efficiently migrate and integrate into damaged tissue when supplied into the bloodstream, and spontaneously differentiate into cells compatible with the homing tissue. Such a repairing action of Muse cells via intravenous injection is recognized in various tissues including the brain, liver, and skin” (Abstract).
Applicant is conflating mechanism of action with therapeutic outcome. The claimed method is treatment of ALS through administration of Muse cells, which is identical to the method taught by Uccelli and Dezawa2. The desired therapeutic outcome is the treatment of ALS. The recitation of how the Muse cells treat ALS does not impart any patentable distinction since the only step required by the claims to treat ALS is administration of the Muse cells. Moreover, for the reasons discussed above, Dezawa2 provides a clear teaching, suggestion, and motivation to treat ALS with Muse cells instead of MSCs.
Conclusion
NO CLAIMS ARE ALLOWED
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/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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