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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12-11-25 has been entered.
Applicant's arguments filed 12-11-25 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. Claims 1-5, 8-11, 15 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Claims 8-11 remain withdrawn.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 remain 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 steps of claim 1 can be delineated using “a)”, “b)” for ease of examination and discussion.
Step b) of claim 1 can be written more clearly as --- administering 1x103 to 1x1011 of the human pluripotent cells/dose into a human that has epidermolysis bullosa (EB) intravenously such that a symptom of the EB is treated---.
It is unclear how administration of the pluripotent cells “recovers” “expression of” collagen VII or collagen XVII genes in epidermis of the human as required in the last 3 lines claim 1.
The last 3 lines of claim 1 use Markush language and set forth the genus of “at least one gene selected from the group consisting of”, but then it goes on to list proteins instead of genes as the species within the genus. The genus should also be ---at least one protein---. To simplify more, just say ---increases expression of collagen VII or XVII---. To simplify even more, the increased expression of collagen VII and XVII at the end of claim 1 can be put together with the therapeutic response for clarity, e.g. ---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---.
Claim Rejections - 35 USC § 112
Written Description
Claims 1-5, 15 remain 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.
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 the human pluripotent cells at 1x103 to 1x1011 human pluripotent cells/dose into a human that has epidermolysis bullosa (EB) intravenously such that 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,
wherein the administration of the human pluripotent cells recovers and/or increases expression of at least one gene selected from the group consisting of Collagen type VII and Collagen type XVII to the epidermis of the human.
The specification lacks written description for administration of pluripotent cells that “recovers” “expression of” Collagen type VII or XVII genes in the epidermis of the human treated with the as required in claim 1. Pg 21, para 32, contemplates “recovering” “expression of” Collagen type VII or XVII genes in the epidermis. But it is unclear what this means. The specification does not teach the patients had decreased expression of collagen VII or XVII in the epidermis. The specification does not teach the patient with EB treated with the pluripotent cells exhibited increased expression of collagen VII or XVII genes in the skin. 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 restored or 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. Applicants’ argument is not persuasive. Pg 21, para 32, contemplates “recovering” “expression of” Collagen type VII or XVII genes in the epidermis. But it is unclear what this means. 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 restored or 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.
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.
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 “provide” them to 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.
Response to arguments
Applicants argue Dezawa taught Muse cells differentiate into skin cells not skin tissue. Applicants’ argument is not persuasive. Skin cells are skin tissue.
Applicants point to a figure of the layers of the skin. Applicants’ argument is not persuasive. The claim does not require forming epidermis, dermis, hypodermis, blood vessels, hair follicles, sweat glands, fibroblasts, lymphatic vessels, and adipose tissue in the organized layers in the figure shown.
Applicants point to Example 1 which describes making a “full-thickness wound” in a mouse and treating it with pluripotent cells. Applicants’ discussion is not an argument.
Applicants point out the MSCs of El-Darouti and the Muse cells of Dezawa are completely different cell types. Applicants’ argument is not persuasive. El-Darouti isolated all bone marrow non-hematopoietic stem cells which inherently MUST comprise Muse cells because that is the first step described by applicants as being part of the invention. The rejection acknowledges the cell types are different and provides motivation to replace the bone marrow non-hematopoietic stem cells of El-Darouti with the Muse cells of Dezawa.
Applicants reiterate the rejection on pg 10-11, point to Ryan who discussed MSCs (pg 11-12), point to El-Darouti who says patients with EB have mutant collagen VII genes (pg 12), and point to Figs. 1B & 5 of Dezawa 2016 (pg 12-13). Applicants’ argument is not persuasive because it does not follow any legal argument or conclude with any legal argument. The combined references teach every limitation claimed. The rejection provides motivation to combine the references. There is reasonable expectation of delivering Muse cells to a patient with EB intravenously such that a symptom of EB is treated and expression of collagen VII or XVII is increased. That is all that is required to establish obviousness.
Applicants disagree with the Examiner’s motivational statement (pg 14). Applicants’ argument is not persuasive. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The Examiner’s motivation to combine references is valid.
Applicants’ discussion of Dewaza and El-Darouti (pg 14-16) are noted but are not persuasive because they do not conclude in any legal argument.
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 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.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638