DETAILED ACTION
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 .
Applicant's arguments filed 6-9-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 6, 7, 12-14 have been canceled. Claim 16 has been added. Claims 1-5, 8-11, 15, 16 remain pending.
Election/Restrictions
Applicants elected Group I, claims 1-7, without traverse on 10-6-21.
Claims 8-11 remain withdrawn.
Claims 1-5, 15, 16 are under consideration.
Claim interpretation
Epidermolysis bullosa (EB) in claim 1 is a group of diseases that cause fragile and blistered skin as a result of collagen 7 deficiency (Table 1; pg 24, para 41; Fig. 3). Claim 1 requires treating EB.
The phrase “non-tumorigenic” in claim 1 has support on pg 10, para 16, line 4-5; pg 19, line 5.
Claim objections
The abbreviation for epidermolysis bullosa “(EB)” was deleted after the first occurrence in claim 1 (line 5); therefore, use of EB in line 7 does not make sense. Put the abbreviation back in on line 5.
Delete “the” in the phrase “the epidermis” in line 6 of claim 1.
The “wherein as the symptom of the epidermolysis bullosa, hair and wound formation are ameliorate” in claim 16 is grammatically incorrect and cannot be deciphered.
Claim Rejections - 35 USC § 112
Written Description
Claim 16 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Withdrawn rejection
The specification lacks written description for increasing collagen VII or XVII in epidermis of a human with EB using pluripotent cells as required in claim 1.
Claim 1 is drawn to: a method of treating epidermolysis bullosa in a human, the method comprising:
isolating human pluripotent cells from mesenchymal tissue; and
administering 1x103 to 1x1011 of the isolated human pluripotent cells/dose into a human that has epidermolysis bullosa intravenously such that expression of collagen type VII or XVII is increased in the epidermis of the human and a symptom of the EB is treated, wherein the pluripotent cells: express SSEA3 and CD105 but not telomerase, are non-tumorigenic, capable of differentiating into ectoderm, endoderm, and mesoderm cells, and capable of self-renewal.
Pg 21, para 32, contemplates “recovering” (i.e. increasing) “expression of” Collagen type VII or XVII genes in the epidermis. However, the specification does not teach the starting expression of collagen VII or XVII in epidermis of EB patients or that treatment with pluripotent cells caused increased expression of collagen VII or XVII genes in the epidermis. Pg 24, para 41, discusses Fig. 3 and says COL7 (human collagen VII) was detectable in epidermis and dermis of “Muse cell-treated” mice, but Fig. 3 and para 41 do not teach COL7 expression was increased as required in claim 1. Pg 25, para 42, discusses Fig. 4 and 5 and says human COL17 was detectable in the skin and epidermis of COL17-knockout mice, but Fig. 4, Fig. 5, and para 42 do not teach COL17 expression was restored or increased as required in claim 1. It is not readily apparent applicants were reasonably in possession of increasing expression of collagen VII or XVII in the epidermis of humans with EB using pluripotent cells as required in claim 1. Accordingly, the concept lacks written description.
Response to arguments
Applicants point to paragraphs 31, 41, 42 and Fig. 3-5. Applicants submit “clearer versions of these figures”, but they look exactly the same as those originally filed. Hardly any detail can be discerned. Applicants’ argument and the Figures are not persuasive. Pg 21, para 32, contemplates “recovering” (i.e. increasing) “expression of” Collagen type VII or XVII genes in the epidermis. However, the specification does not teach the starting expression of collagen VII or XVII in epidermis of EB patients or that treatment with pluripotent cells caused increased expression of collagen VII or XVII genes in the epidermis. Pg 24, para 41, discusses Fig. 3 and says COL7 (human collagen VII) was detectable in epidermis and dermis of “Muse cell-treated” mice, but Fig. 3 and para 41 do not teach COL7 expression was increased as required in claim 1. Pg 25, para 42, discusses Fig. 4 and 5 and says human COL17 was detectable in the skin and epidermis of COL17-knockout mice, but Fig. 4, Fig. 5, and para 42 do not teach COL17 expression was restored or increased as required in claim 1.
Applicants point to Fig. 1F, 1G, and 2 of Fujita (2021) as post-filing evidence that muse-treated mice exhibited increased COL7 and COL17 expression. Applicants’ argument is not persuasive. The description of Fig. 1F and 1G is missing from the caption of Fig. 1, and there is nothing in Fig. 1F or 1G that shows before and after pictures of the epidermis of the muse-cell treated mice. The various conditions represented in the Figures cannot be discerned because the picture quality is too poor. Figure 2 describes muse-treated mice exhibited COL7 and COL17, but not that it was in the epidermis or that it was increased as compared to prior to treatment. A review of Supplemental Fig. S3 in Fujita online shows Muse-treated mouse epidermal tissue expressed human COL7 and human COL17. It does not say COL7 and COL17 expression increased as claimed. And the expression/existence of hCOL7 or hCOL17 in mouse epidermal tissue was not “increased” per se because the human proteins did not exist in the mouse tissue. There is nothing in Fujita that says the overall expression of human and mouse COL7 or COL17 increased as compared. The existence of hCOL7 or hCOL17 in mouse epidermal tissue after Muse treatment is not the same thing as “increased expression” of COL7 or COL17 as claimed.
New rejection
The specification lacks written description for “wherein as the symptom of the epidermolysis bullosa, hair and wound formation are ameliorate” in claim 16. The claim is grammatically incorrect and cannot be deciphered. The specification does not teach treating a symptom of EB, increasing expression of collagen VII or XVIII, and ameliorating anything about the patients’ hair or wound. Accordingly, the concept lacks written description. Applicants point to support for claim 16 on pg 11, last paragraph, in paragraph 30 of the disclosure and in the Examples. Paragraph 30 on pg 20 of the original disclosure does not contemplate treating hair or wound formation. Support cannot be found for treating hair “formation” or wound “formation” as required in claim 16 anywhere in the specification as originally filed other than administering Muse cells intravenously to treat skin wounds.
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.
Claim 16 is 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.
The “wherein as the symptom of the epidermolysis bullosa, hair and wound formation are ameliorate” in claim 16 is grammatically incorrect and cannot be deciphered. Therefore, those of skill would not be able to determine the metes and bounds of the phrase or determine when they were infringing on the claim.
Claim Rejections - 35 USC § 103
Pending rejections
A) Claims 1, 4, 5, 15 remain rejected under 35 U.S.C. 103 as being unpatentable over El-Darouti (Dermatol. Ther., 2016, Vol. 29, No. 2, pg 96-100) in view of Dezawa (20120244129) and evidenced by Gregory (Exp. Cell Res., 2005, pg 330-335) and Dezawa (20120244129).
This is a two-way obviousness rejection. Either El-Darouti or Dezawa can be used as the primary reference.
El-Darouti isolated bone marrow non-hematopoietic stem cells from a human (“NHBMSCs”; Patients and Methods) and injected them into humans with EB intravenously such that treatment occurs. (“NHBMSCs”; Patients and Methods; “IV” = intravenous). The NHBMSCs of El-Darouti are bone marrow MSCs (BM-MSCs) as evidenced by Gregory (abstract; pg 331 MSCs from bone marrow).
El-Darouti did not teach isolating pluripotent cells from and administering a dose of 1x103-1x1011 pluripotent cells as required in claim 1.
However, Dezawa isolated adult human mesenchymal tissue (e.g. bone marrow) and isolated Muse cells from the tissue (pg 14, Example 1, “Preparation and characterization of muse-enriched cell fractions and M-Clusters”; para 7, 13, 17; pg 3, item 13; para 48, 49). Dezawa taught Muse cells are pluripotent, express SSEA3 & CD105, have low/no telomerase activity (claim 16), differentiate into mesoderm, endoderm, ectoderm (claim 7), do not form neoplasms (“do not show tumorigenic proliferative activity” para 18), and self-renew (para 13, 16). The dose of 1x103-1x1011 cells in claim 1 is an obvious variant of the dosage described by Dezawa in paragraphs 159 and 170 because Dezawa taught “the dose can be appropriately determined depending on an organ to be regenerated, a tissue type, or size” (para 159) and “specified based on the number of cells to be administered, for example, and appropriately determined depending on disease types or severity” (para 170). The dosage of 1x103-1x1011 cells in claim 1 was obvious because it well-within the skilled artisan’s design choice.
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to administer Muse cells to a human with EB as described by El-Darouti by first isolating mesenchymal tissue followed by isolating Muse cells from the tissue described by Dezawa. Those of ordinary skill in the art at the time of filing would have been motivated to isolate mesenchymal tissue followed by enriching for Muse cells to increase the differentiation capability of the cells used for treatment. Those of ordinary skill in the art at the time of filing would have been motivated to isolate mesenchymal tissue followed by enriching for Muse cells to treat disease because it is specifically taught by Dezawa in paragraphs 160, 162, 164, et al. Motivation to specifically treat skin damage is discussed by Dezawa in paragraphs 23, 154, 160, 162.
The Muse cells of Dezawa inherently MUST secrete keratin 14 and cause increase collagen VII and collagen XVII expression in the epidermis of the EB patient as required in claim 1 because they are the same cells used by applicants.
Those of skill would have had a reasonable expectation of successfully treating EB using only pluripotent Muse cells because El-Darouti used a cell population comprising multipotent cells and pluripotent Muse cells and because pluripotent Muse cells alone have increased differentiation capability than the cell population of El-Darouti.
In the reverse, Dezawa taught isolating mesenchymal tissue from adult humans followed enriching for Muse cells and administering the Muse cells to humans with various diseases such as Parkinson’s disease, brain infarction, spinal cord injury, myodystropathy (para 162). An organ to be regenerated include, but are not limited to, bone marrow, spinal cord, blood, spleen, liver, lungs, bowel, eyes, brain, immune system, circulatory system, bone, connective tissue, muscle, heart, blood vessel, pancreas, central nervous system, peripheral nervous system, kidney, bladder, skin, epithelial appendages, breast-mammary gland, adipose tissue, and mucous membranes of mouth, esophagus, vagina, and anus, for example. Also, examples of diseases to be treated therein include, cancer, cardiovascular disease, metabolic disease, hepatic disease, diabetes mellitus, hepatitis, haemophilia, blood system disease, degenerative or traumatic neurologic disorder such as spinal cord injury, autoimmune disease, genetic defects, connective tissue disease, anemia, infectious disease, graft rejection, ischaemia, inflammation, and damage to skin or muscle (para 160).
Dezawa did not teach administering a dose of 1x103-1x1011 Muse cells to a human with EB as required in claim 1.
However, the dose of 1x103-1x1011 cells in claim 1 is an obvious variant of the dosage described by Dezawa in paragraphs 159 and 170 because Dezawa taught “the dose can be appropriately determined depending on an organ to be regenerated, a tissue type, or size” (para 159) and “specified based on the number of cells to be administered, for example, and appropriately determined depending on disease types or severity” (para 170). The dosage of 1x103-1x1011 cells in claim 1 was obvious because it well-within the skilled artisan’s design choice. In addition, El-Darouti treated patients with EB using bone marrow cells (NHBMSCs for reasons cited above) that inherently comprised Muse cells. The NHBMSCs inherently MUST contain Muse cells having the structure set forth in step a) of claim 1 because applicants say bone marrow derived MSCs contain Muse cells on pg 13, para 22. Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to isolate mesenchymal tissue from a human followed by enriching for Muse cells and administering them to treat skin disease as described by Dezawa, specifically to a human with EB as described by El-Darouti. Those of ordinary skill in the art at the time of filing would have been motivated to use isolated Muse cells of Dezawa to treat EB instead of the NHBMSCs described by El-Darouti because of their increased potency.
The Muse cells of Dezawa inherently MUST secrete keratin 14, collagen VII and collagen XVII and their expression must increase in the epidermis as required in claim 1 because they are the same cells used by applicants.
All dystrophic epidermolysis bullosa is either dominant or recessive as required in claim 5.
Dezawa taught isolating mesenchymal cells from an adult human followed by enriching for pluripotent Muse cells as required in claim 15.
Claim 16 has been included because the combined teachings disclose treating wounds and because the metes and bounds are unclear.
Response to arguments
Applicants argue the cited references fail to provide motivation to combine the teachings with a reasonable expectation of increasing COL7 or COL17. Applicants’ argument is not persuasive. The statement conflates arguments. Motivation to combine need not come from the references, and motivation to combine the references is clearly set part as part of the rejection. If applicants believe those motivational statements to be inadequate, then that argument has not been made. Applicants attempt to argue a lack of “reasonable expectation of success” is incomplete and unfounded. In this case, those of skill would have had a reasonable expectation of successfully treating EB using only pluripotent Muse cells because El-Darouti used a cell population comprising multipotent cells and pluripotent Muse cells and because pluripotent Muse cells alone have increased differentiation capability than the cell population of El-Darouti.
Applicants’ argument regarding “mechanism of action” on pg 10 of the response filed 6-9-26 is not persuasive. There is no mechanism of action in the claim. The Muse cells of Dezawa inherently MUST secrete keratin 14 and cause increase collagen VII and collagen XVII expression in the epidermis as required in claim 1 because they are the same cells used by applicants.
Applicants argue repairing skin in EB patients is highly complex because of architecture of the layers (pg 10, 2nd full para). Applicants’ argument is not persuasive. El-Darouti isolated bone marrow non-hematopoietic stem cells from a human and injected them into humans with EB intravenously such that treatment occurs. It was well-known that the skin of EB patients responds to therapy comprising multipotent cells and pluripotent Muse cells as described by El-Darouti.
The 3rd para on pg 10 says all limitations are not taught. Applicants’ argument is not persuasive because it is unclear which limitation is missing. All limitations are discussed in the rejection.
Applicants argue Fujita shows unexpected results because increased COL7 and COL17 occurred in the skin of Muse-treated mice. Applicants’ argument is not persuasive. Applicants point to Fig. 1F, 1G, and 2 of Fujita (2021) as post-filing evidence that muse-treated mice exhibited increased COL7 and COL17 expression. However, the description of Fig. 1F and 1G is missing from the caption of Fig. 1, and there is nothing in Fig. 1F or 1G that shows before and after pictures of the epidermis of the muse-cell treated mice. The various conditions represented in the Figures cannot be discerned because the picture quality is too poor. Figure 2 describes muse-treated mice exhibited COL7 and COL17, but not that it was in the epidermis or that it was increased as compared to prior to treatment. A review of Supplemental Fig. S3 in Fujita online shows Muse-treated mouse epidermal tissue expressed human COL7 and human COL17. It does not say COL7 and COL17 expression increased as claimed. And the expression/existence of hCOL7 or hCOL17 in mouse epidermal tissue was not “increased” per se because the human proteins did not exist in the mouse tissue. There is nothing in Fujita that says the overall expression of human and mouse COL7 or COL17 increased as compared. The existence of hCOL7 or hCOL17 in mouse epidermal tissue after Muse treatment is not the same thing as “increased expression” of COL7 or COL17 as claimed. The existence of hCOL7 or hCOL17 in epidermal tissue of mice treated with human Muse cells is also not “unexpected” because the Muse cells differentiate and express human COL7 and COL17.
Applicants compare Fig. 1B of El-Darouti which shows results after 15 weeks using MSCs vs. Fig. 4 of the instant application which shows results after 4 weeks using Muse cells. Applicants’ argument is not persuasive. The rejection is based on El-Darouti’s teaching of using bone marrow non-hematopoietic stem cells from a human (“NHBMSCs”; Patients and Methods). There is nothing in El-Darouti about the results after 4 weeks, so the comparison is inapt, and a conclusion that applicants’ results would be better than El-Darouti’s after 4 weeks is unfounded. There is nothing in applicants results at 15 weeks, so it cannot be said that applicants’ results were better than El-Darouti’s at 15 weeks. This line of reasoning is illogical.
B) Claims 2 and 3 remain rejected under 35 U.S.C. 103 as being unpatentable over El-Darouti (Dermatol. Ther., 2016, Vol. 29, No. 2, pg 96-100) in view of Dezawa (20120244129) and evidenced by Gregory (Exp. Cell Res., 2005, pg 330-335) and Dezawa (20120244129) as applied to claims 1, 4, 5, 15, 16 and further in view of Fine (Orphanet J. Rare Diseases, 2010, Vol. 5, No. 12, pg 1-17).
The combined teachings of El-Darouti, Dezawa and Gregory prepared and administered human Muse cells to a human who had epidermolysis bullosa intravenously such that treatment occurred as encompassed by claims 1, 4, 5, 15 for reasons cited in the rejection directly above.
The combined teachings of El-Darouti, Dezawa and Gregory did not teach the epidermolysis bullosa was epidermolysis bullosa simplex or junctional epidermolysis bullosa as required in claims 2 or 3.
However, Fine taught epidermolysis bullosa encompassed numerous variations and stages including epidermolysis bullosa simplex or junctional epidermolysis bullosa.
Thus it would have been obvious to those of ordinary skill in the art at the time of filing to administer Muse cells to patients with EB as described by El-Darouti, Dezawa, and Gregory wherein the EB was EB simplex or junctional EB as required in claim 2 or 3. Those of ordinary skill in the art at the time of filing would have been motivated to do so to relieve the skin lesions in those patients.
Response to arguments
Applicants do not specifically address this rejection.
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 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.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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