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 .
Claims 2, 9, 13, 14, 16-26, 28-46 have been canceled. Claims 47 and 48 have been added. Claims 1, 3-8, 10-12, 15, 27, 47, 48 are pending.
Election/Restrictions
Applicants elected Group I, claims 1-12, 14-16, 27, without traverse in the reply filed on 12-17-25.
Claims 1, 3-8, 10-12, 15, 27, 47, 48 are under consideration.
Claim objections
The term “subject” in the phrase “human subject” in claim 1 is redundant. Just say ---human---.
The “implanting” of KPCs into human skin in step c) does not have a nexus with the concept of “preparing a hair follicle” as required at the end of step c) or the preamble of claim 1. If the KPCs are being implanted into a hair follicle to “prepare” that hair follicle, then the KPCs should be implanted into a human hair follicle, and the preamble should reflect that. If the KPCs are being implanted into human skin such that a hair follicle forms, then the KPCs should be implanted into human skin such that a hair follicle forms; the preamble should be ---A method of making a hair follicle, the method comprising---.
It is unclear why the preparation of hiPS cells is part of claim 1.
The phrase “to obtain keratinocyte progenitor cells (KPCs)” in claim 1 is an intended use and does not necessarily have to occur. Therefore, there is no clear positive step indicating the “differentiating” of iPS cells must result in the production of KPCs.
The phrase “to obtain embryoid bodies (EBs)” in claim 1 is an intended use and does not necessarily have to occur. Therefore, there is no clear positive step indicating the “culturing” of iPS cells must result in the production of EBs.
It is unclear whether the two steps of i) and ii) are the “period of 16-18 days” in claim 1 or whether just the step of culturing EBs on substrate occurs for 16-18 days.
The phrase “thereby preparing the hair follicle” in the phrase “implanting the KPCs into skin of a human subject, thereby preparing the hair follicle” equivalates implanting KPCs into human skin with making a hair follicle without clearly saying a hair follicle is obtained. Merely implanting KPCs into human skin is not “making a hair follicle”. Perhaps applicants are attempting to claim functional language, i.e. ---implanting the KPCs into skin of a human subject such that a hair follicle is formed---. Or perhaps applicants are attempting to say the KPCs are implanted into an established hair follicle, i.e. “implanting the KPCs into a hair follicle of a human subject---. Regardless, the phraseology is ambiguous and unclear (see 112/2nd).
The steps of claim 1 are out of order and require simplification, e.g. ---A method of making a hair follicle, the method comprising:
a) floating human induced pluripotent stem (iPS) cells in culture such that embryoid bodies (EBs) are obtained;
b) culturing the EBs on a substrate such that keratinocyte progenitors are obtained; and
c) implanting the keratinocyte progenitors into human skin [such that a hair follicle is obtained?]---.
The phrase “non-integrating episomal” in the phrase “non-integrating episomal plasmid” in claim 4 is redundant because plasmids are defined as being non-integrating and episomal.
The term “vectors” in the phrase “plasmid vectors” is redundant; the phrase can be simplified as ---plasmids---.
The term “p53 1” in claim 4 appears to have a typo; it should just be p53.
The phrase “shRNA for human p53 1” in claim 4 is inaccurate and fails to capture the fact that the shRNA binds p53 or inhibits p53 expression.
Claim 4 is missing the fact that the fibroblasts are isolated or human.
Claim 4 is grammatically awkward and does not contain a clear, positive indication that introducing plasmids encoding Oct4, Sox2, Klf4, L-Myc, and shRNA that binds p53 into isolated human fibroblasts results in iPS cells, e.g. ---introducing plasmids encoding Oct4, Sox2, Klf4, L-Myc, and shRNA that binds p53 into isolated human fibroblasts such that the hiPS cells are obtained---.
Claim 6 can be written more simply and accurately as ---wherein the hiPSCs are floated in culture for 5-6 days and the EBs are cultured on a substrate for 10-13 days---.
Claim 7 is awkward because it is unclear whether the collagen or the plate is the substrate. Claim 7 can be written more clearly as ---wherein the substrate is collagen---.
Claim 8 is awkward because it is unclear whether the collagen or the plate is the substrate. Claim 8 can be written more clearly as ---wherein the collagen is collagen type I---.
Claim 10 can be written more simply and accurately as ---wherein the hiPSCs are floated in culture in the presence of all-trans retinoic acid (ATRA), bone morphogenic protein 4 (BMP4) and epidermal growth factor (EGF); and/or the EBs are cultured on a substrate in the presence of BMPR and EGF---.
Claim 11 can be written more simply and accurately as ---wherein the EBs are cultured on a substrate in the presence of ATRA for 7 days---.
Claim 12 can be written more simply and accurately as ---wherein the keratinocyte progenitors are implanted by intradermal injection---.
Claim 15 can be written more simply and accurately as ---wherein the keratinocyte progenitors do not express KRT5 or KRT14---.
Claim 27 has the same problems as claim 1.
Claim 47 can be written more simply and accurately as ---wherein the keratinocyte progenitors are implanted by intradermal injection---.
Claim 48 has the same problems as claims 1 and 47 and dependent claims incorporated therein.
These suggestions are not meant to indicate allowable subject matter because of the number of remaining rejections.
Claim Rejections - 35 USC § 112
Written Description
Claims 1, 3-8, 10-12, 15, 27 remain and claims 47, 48 are 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 rejection regarding any pluripotent cell that expresses CD200, ITGA6, ITGB1, OCT4, NANOG, SOX2, TRA160, TRA181, SSEA4 as broadly encompassed by claim 2 has been withdrawn because the claim has been canceled.
The rejection regarding differentiating pluripotent cells into HFBSCs comprising forming EBs in floating culture as required in claim 6 has been withdrawn in view of the amendment.
The rejection regarding making a hair follicle by differentiating pluripotent cells into keratinocytes as required in claim 9 has been withdrawn because the claim has been canceled.
The rejection regarding implanting cells “15-19 [or 16-18] days in vitro (DIV)” in claim 12 has been withdrawn in view of the amendment which just says implanting is by intradermal injection.
Pending rejection
A) The specification lacks written description for obtaining any KPCs as broadly encompassed by claims 1, 27, 48.
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Claim 48 is drawn to:
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The step of preparing iPS cells in step a) of claims 1, 27 and 48 was well known: somatic cells are dedifferentiated into pluripotent cells using reprogramming factors. iPS cells are structurally different than normally occurring pluripotent cells in an embryo or adults (MAPCs). See Lubusca (World J Stem Cells, 2019, Vol. 11, No. 1, pg 1-12) for a summary of iPS cells, ES cells in vivo, ES cell lines, and adult pluripotent cells.
The concept of differentiating iPS cells into any keratinocyte progenitor in claims 1, 27 and 48 lacks written description. The metes and bounds of “keratinocyte progenitor cells (KPCs)” cannot be determined because the specification and the art at the time of filing do not define KPCs. The specification contemplates “hair follicle bulge stem cells (HFBSCs)” (pg 1, para 3, and throughout the disclosure and examples). However, the “bulge” of a hair follicle is simply a location within a hair follicle. Any hair follicle stem cell can be put into the “bulge” of a hair follicle and be considered an HFBSC. Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16) taught differentiating hiPS cells into HFBSCs and implanting them into the skin of a human as required in claim 1 (abstract) but did not teach the metes and bounds of HFBSCs. Pg 34-35 discusses “Generation, Characterization, & Differentation of hiPSCs into HFBSCs” without defining the metes and bounds of HFBSCs. Expression analysis of HFBSCs involving CD200, ITGA6, ITGB1, CD63, Nanog, Oct4, is discussed (para 131-133) without clearly setting forth the structures that define HFBSCs or the function/potency of HFBSCs. The specification does not correlate the structure/function/potency of HFBSCs to any hair follicle stem cell that was well known in the art. It is unclear whether these undefined HGBSCs described by Ibrahim and applicants’ disclosure are KPCs as required in claims 1, 27, 48.
Ohyama (J. Derm. Sci. 2007, Vol. 46, No. 2, pg 81-89) taught the hair follicle bulge is a reservoir for epithelial stem cells and keratin stem cells (KSCs). Therefore, KSCs encompass well-known KSCs described by Ohyama but not epithelial stem cells. KSCs also encompass any other stem cell capable of becoming a keratinocyte.
Therefore, those of skill would not be able to determine when they had arrived at KPCs as required in claims 1, 27, 48. Those of skill would not be able to determine how to use KPCs, specifically HGBSCs expressing CD200, ITGA6, ITGB1, CD63, KRT18, KRT19, KRT15 as shown in Fig. 1, because the specification and Ibrahim do not teach the function or potency of the stem cells or compare the structures/functions of keratinocyte progenitors that were well known in the art. Accordingly, the concept of keratinocyte progenitors in claims 1, 27, and 48 lacks written description.
The final step of claims 1, 27, and 48 requires implanting HFBSCs into the skin of a human. While the preamble encompasses growing any hair follicle anywhere, claim 1 is limited to treatment because treatment is the sole disclosed use for implanting HFBSCs into the skin of a human (pg 2, line 4; pg 10, para 34; et al).
The “Experimental Section” on pg 12-32 of the specification appears to set forth protocols.
The “Results” section on pg 33-46 reveals the results of the experiments.
Pg 13 (para 64-66) and pg 18-28 discuss differentiation of pluripotent cells into HFBSCs without defining when KPCs have been obtained. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1.
Pg 14 (para 67-68) says the HFBSCs were characterized using antibodies that bind Oct4, P63, KRT15, KRT19, KRT8, KRT18, KRT5, and KRT14 at days 0, 11, 18, 25. These antibodies are not the same profile as those in Fig. 1. However, it is unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 14-15 (para 69-70) discusses culturing HFBSCs with mouse dermal cells but does not teach the specifics of the outcome, how/whether the HFBSCs differentiate, or the structure/function of the cells obtained from these protocols. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 15 (para 71-72) and pg 28-32 discusses transplanting HFBSCs into dogs.
Pg 33-34 discusses obtaining iPS cells which was well-known in the art.
Pg 34-35 discusses differentiation of iPS cells into HFBSCs and characterizing HFBSCs. Again, applicants point to Fig. 1 and 4 and 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1.
Figures 2 and 9 are discussed on pg 34-35, but it is unclear how the expression patterns claimed correlate to any well-known hair follicle stem cell or any newly discovered stem cell. If the cells observed are new, then applicants fail to teach the function or potency of the new cells or how they compare to well-known hair follicle stem cells.
Pg 35-37 discusses the “Expression Dynamic of the Molecules Determining hiPSC-HFBSC fate”. Pg 35, para 137, says ITGA6, ITGB1, and CD200 are “critical for consummation of HFBSC generation”, but claim 1 does not require expression of either protein. Oct4 expression decreased and P63, KRT15, KRT19, and KRT8 expression increased (para 138, 140) which is missing from the claims. Moreover, it is unclear what function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8.
Pg 38 (para 143) characterizes keratinocytes derived from HFBSCs. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 38, para 147, discusses a “bulge activation hypothesis”.
Pg 39-42 describes “Characterization in vivo of hiPSC-HFBSCs following transplantation”. Applicants obtained hair follicles from the HFBSCs implanted into the skin of mice but only in the presence of MDCs (mouse dermal cells) (pg 41, line 3). Applicants did not obtain human hair. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 42-46 describes “Assessing the necessary & sufficient elements for HF generation”. One sentence say “all of the seven molecules (markers) required for complete HF generation were also fundamental to the earliest stages of normal development” without teaching the 7 essential markers. Fig. 1 shows 7 markers (ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63), but they are not in the claim. It is also unclear what specific function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8.
Accordingly, claims 1, 27, 48 lack written description.
B) The specification lacks written description for KPCs expressing ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63 as broadly encompassed by claim 3. Pg 42-46 describes “Assessing the necessary & sufficient elements for HF generation”. One sentence say “all of the seven molecules (markers) required for complete HF generation were also fundamental to the earliest stages of normal development” without teaching the 7 essential markers. Fig. 1 shows 7 markers (ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63); however, it is unclear what specific function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8. Accordingly, the concept any cell expressing ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8 being any “keratinocyte progenitor” as required in claim 3 lacks written description.
C) The specification lacks written description for culturing EBs on any substrate as broadly encompassed by claims 1, 27, 48 or any collagen as broadly encompassed by claim 7 other than collagen I (claim 8). Claims 1, 27, 48 require culturing EBs on any substrate. Claim 7 is limited to the substrate being any collagen. Claim 8 is limited to the substrate being collagen I. The specification is limited to the substrate being collagen I (para 6, 30, 39, 65, 66, pg 18, step 7; pg 19, item 2; pg 22, day 7; pg 23, item 10, et al). The specification fails to correlate collagen coated plates to any other substrate as broadly encompassed by claims 1, 27, 48 or any collagen as broadly encompassed by claim 7. Accordingly, the concept lacks written description other than collagen I.
D) The specification lacks written description for culturing pluripotent cells in ATRA, BMP4, and EGF such that EBs form or culturing EBs in BMP4 and EGF such that KPCs form as broadly encompassed by claim 10. Fig. 1 is limited to culturing pluripotent cells in EGF, ATRA, and BMP4 in floating culture such that EBs are formed. EBs are plated on collagen I coated plates and cultured in the presence of EGF, ATRA, and BMP4 until day 12. ATRA is removed on day 12 and the HFBSCs are cultured in EGF and BMP4. “HFBSCs” expressing 7 markers occur on days 11-18. Both steps are and all reagents are required for “HFBSCs” expressing the 7 markers to occur. Accordingly, the concept in claim 10 lacks written description as broadly written.
E) The specification lacks written description for making hair follicle cells in vivo as encompassed by claim 1, 27, 48. The claims encompass treating hair loss, alopecia,… or epidermolysis bullosa (original claim 16). The specification fails to teach creating any hair in vivo. The specification does not teach any of the methods resulted in hair formation in vivo. The specification does not teach performing the method in any animal model of hair loss, alopecia,… or epidermolysis bullosa as broadly encompassed by claims 1, 27, 48 or that the method results in hair formation in vivo. Accordingly, making hair follicles for the purpose of making hair in vivo as broadly encompassed by claims 1, 27, 48 lacks written description.
New rejection
F) The specification lacks written description for differentiating iPS cells into KPCs for 16-18 days comprising floating iPS cells in culture such that EBs are obtained and culturing the EBs such that KPCs are obtained as encompassed by claims 1, 27, 48. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 for support, but none can be found. The specification does not teach the combination of floating iPS cells to make EBs and culturing EBs to make HFBSCs or any other keratinocyte progenitor occurs within 16-18. The concept is not contemplated; therefore, the concept lacks written description.
G) The specification lacks written description for floating iPS cells in culture for 5-6 days such that EB are obtained or culturing EBs for 10-13 days such that KPCs are obtained as required in claim 6. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 for support, but none can be found.
Response to arguments
Applicants point to case law which is not persuasive because the fact patterns are not the same.
Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 (pg 7) which are not persuasive for reasons set forth in the basis of the rejection.
Applicants’ discussion of dependent claims on pg 8-10 is noted but not persuasive for reasons set forth in the rejections.
Enablement
Claims 1, 3-8, 10-12, 15, 27 remain and claims 47, 48 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 differentiating isolated human pluripotent cells into hair follicle stem cells and implanting them into a mammal, does not reasonably provide enablement for the method of claim 1 as broadly claimed or using the method to create hair or treat hair loss as broadly encompassed by claims 1, 16, 27. 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/use the invention commensurate in scope with these claims.
Withdrawn rejections
The rejection regarding any pluripotent cell that expresses CD200, ITGA6, ITGB1, OCT4, NANOG, SOX2, TRA160, TRA181, SSEA4 as broadly encompassed by claim 2 has been withdrawn because the claim has been canceled.
The rejection regarding differentiating pluripotent cells into HFBSCs comprising forming EBs in floating culture as required in claim 6 has been withdrawn in view of the amendment.
The rejection regarding making a hair follicle by differentiating pluripotent cells into keratinocytes as required in claim 9 has been withdrawn because the claim has been canceled.
The rejection regarding implanting cells “15-19 [or 16-18] days in vitro (DIV)” in claim 12 has been withdrawn in view of the amendment which just says implanting is by intradermal injection.
Pending rejections
A) The specification does enable obtaining any KPCs as broadly encompassed by claims 1, 27, 48.
Claims 1, 27 and 48 are recited above.
The step of preparing iPS cells in step a) of claims 1, 27 and 48 was well known as discussed above.
The concept of differentiating iPS cells into any keratinocyte progenitor in claims 1, 27 and 48 is not enabled. The metes and bounds of “keratinocyte progenitor cells (KPCs)” cannot be determined because the specification and the art at the time of filing do not define KPCs. The specification contemplates “hair follicle bulge stem cells (HFBSCs)” (pg 1, para 3, and throughout the disclosure and examples). However, the “bulge” of a hair follicle is simply a location within a hair follicle. Any hair follicle stem cell can be put into the “bulge” of a hair follicle and be considered an HFBSC. Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16) taught differentiating hiPS cells into HFBSCs and implanting them into the skin of a human as required in claim 1 (abstract) but did not teach the metes and bounds of HFBSCs. Pg 34-35 discusses “Generation, Characterization, & Differentation of hiPSCs into HFBSCs” without defining the metes and bounds of HFBSCs. Expression analysis of HFBSCs involving CD200, ITGA6, ITGB1, CD63, Nanog, Oct4, is discussed (para 131-133) without clearly setting forth the structures that define HFBSCs or the function/potency of HFBSCs. The specification does not correlate the structure/function/potency of HFBSCs to any hair follicle stem cell that was well known in the art. It is unclear whether these undefined HGBSCs described by Ibrahim and applicants’ disclosure are KPCs as required in claims 1, 27, 48.
Ohyama (J. Derm. Sci. 2007, Vol. 46, No. 2, pg 81-89) taught the hair follicle bulge is a reservoir for epithelial stem cells and keratin stem cells (KSCs). Therefore, KSCs encompass well-known KSCs described by Ohyama but not epithelial stem cells. KSCs also encompass any other stem cell capable of becoming a keratinocyte.
Therefore, the specification fails to enable those of skill to determine when they had arrived at KPCs as required in claims 1, 27, 48. Those of skill would not be able to determine how to use KPCs, specifically HGBSCs expressing CD200, ITGA6, ITGB1, CD63, KRT18, KRT19, KRT15 as shown in Fig. 1, because the specification and Ibrahim do not teach the function or potency of the stem cells or compare the structures/functions of keratinocyte progenitors that were well known in the art. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use keratinocyte progenitors in claims 1, 27, and 48.
The final step of claims 1, 27, and 48 requires implanting HFBSCs into the skin of a human. While the preamble encompasses growing any hair follicle anywhere, claim 1 is limited to treatment because treatment is the sole disclosed use for implanting HFBSCs into the skin of a human (pg 2, line 4; pg 10, para 34; et al).
The “Experimental Section” on pg 12-32 of the specification appears to set forth protocols.
The “Results” section on pg 33-46 reveals the results of the experiments.
Pg 13 (para 64-66) and pg 18-28 discuss differentiation of pluripotent cells into HFBSCs without defining when KPCs have been obtained. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1.
Pg 14 (para 67-68) says the HFBSCs were characterized using antibodies that bind Oct4, P63, KRT15, KRT19, KRT8, KRT18, KRT5, and KRT14 at days 0, 11, 18, 25. These antibodies are not the same profile as those in Fig. 1. However, it is unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 14-15 (para 69-70) discusses culturing HFBSCs with mouse dermal cells but does not teach the specifics of the outcome, how/whether the HFBSCs differentiate, or the structure/function of the cells obtained from these protocols. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 15 (para 71-72) and pg 28-32 discusses transplanting HFBSCs into dogs.
Pg 33-34 discusses obtaining iPS cells which was well-known in the art.
Pg 34-35 discusses differentiation of iPS cells into HFBSCs and characterizing HFBSCs. Again, applicants point to Fig. 1 and 4 and 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1.
Figures 2 and 9 are discussed on pg 34-35, but it is unclear how the expression patterns claimed correlate to any well-known hair follicle stem cell or any newly discovered stem cell. If the cells observed are new, then applicants fail to teach the function or potency of the new cells or how they compare to well-known hair follicle stem cells.
Pg 35-37 discusses the “Expression Dynamic of the Molecules Determining hiPSC-HFBSC fate”. Pg 35, para 137, says ITGA6, ITGB1, and CD200 are “critical for consummation of HFBSC generation”, but claim 1 does not require expression of either protein. Oct4 expression decreased and P63, KRT15, KRT19, and KRT8 expression increased (para 138, 140) which is missing from the claims. Moreover, it is unclear what function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8.
Pg 38 (para 143) characterizes keratinocytes derived from HFBSCs. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 38, para 147, discusses a “bulge activation hypothesis”.
Pg 39-42 describes “Characterization in vivo of hiPSC-HFBSCs following transplantation”. Applicants obtained hair follicles from the HFBSCs implanted into the skin of mice but only in the presence of MDCs (mouse dermal cells) (pg 41, line 3). Applicants did not obtain human hair. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 42-46 describes “Assessing the necessary & sufficient elements for HF generation”. One sentence say “all of the seven molecules (markers) required for complete HF generation were also fundamental to the earliest stages of normal development” without teaching the 7 essential markers. Fig. 1 shows 7 markers (ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63), but they are not in the claim. It is also unclear what specific function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8.
Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make any KPCs and use them to make hair follicles in vivo as required in claims 1, 27, 48.
B) The specification does not enable making/using KPCs expressing ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63 as broadly encompassed by claim 3. Pg 42-46 describes “Assessing the necessary & sufficient elements for HF generation”. One sentence say “all of the seven molecules (markers) required for complete HF generation were also fundamental to the earliest stages of normal development” without teaching the 7 essential markers. Fig. 1 shows 7 markers (ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63); however, it is unclear what specific function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use a cell expressing ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8 as any “keratinocyte progenitor” as required in claim 3.
C) The specification does not enable culturing EBs on any substrate as broadly encompassed by claims 1, 27, 48 or any collagen as broadly encompassed by claim 7 other than collagen I (claim 8). Claims 1, 27, 48 require culturing EBs on any substrate. Claim 7 is limited to the substrate being any collagen. Claim 8 is limited to the substrate being collagen I. The specification is limited to the substrate being collagen I (para 6, 30, 39, 65, 66, pg 18, step 7; pg 19, item 2; pg 22, day 7; pg 23, item 10, et al). The specification fails to correlate collagen coated plates to any other substrate as broadly encompassed by claims 1, 27, 48 or any collagen as broadly encompassed by claim 7. Accordingly, the concept is not enabled other than collagen I.
D) The specification does not enable culturing pluripotent cells in ATRA, BMP4, and EGF such that EBs form or culturing EBs in BMP4 and EGF such that KPCs form as broadly encompassed by claim 10. Fig. 1 is limited to culturing pluripotent cells in EGF, ATRA, and BMP4 in floating culture such that EBs are formed. EBs are plated on collagen I coated plates and cultured in the presence of EGF, ATRA, and BMP4 until day 12. ATRA is removed on day 12 and the HFBSCs are cultured in EGF and BMP4. “HFBSCs” expressing 7 markers occur on days 11-18. Both steps are and all reagents are required for “HFBSCs” expressing the 7 markers to occur. Accordingly, the concept in claim 10 is not enabled as broadly written.
E) The specification does not enable making hair follicle cells in vivo as encompassed by claim 1, 27, 48. The claims encompass treating hair loss, alopecia,… or epidermolysis bullosa (original claim 16). The specification fails to teach creating any hair in vivo. The specification does not teach any of the methods resulted in hair formation in vivo. The specification does not teach performing the method in any animal model of hair loss, alopecia,… or epidermolysis bullosa as broadly encompassed by claims 1, 27, 48 or that the method results in hair formation in vivo. Accordingly, making hair follicles for the purpose of making hair in vivo as broadly encompassed by claims 1, 27, 48 is not enabled.
New rejections
F) The specification lacks written description for differentiating iPS cells into KPCs for 16-18 days comprising floating iPS cells in culture such that EBs are obtained and culturing the EBs such that KPCs are obtained as encompassed by claims 1, 27, 48. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 for support, but none can be found. The specification does not teach the combination of floating iPS cells to make EBs and culturing EBs to make HFBSCs or any other keratinocyte progenitor occurs within 16-18. The concept is not contemplated; therefore, the concept lacks written description.
G) The specification does not enable floating iPS cells in culture for 5-6 days such that EB are obtained or culturing EBs for 10-13 days such that KPCs are obtained as required in claim 6. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 for support, but none can be found.
Response to arguments
Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 (pg 11-12) which are not persuasive for reasons set forth in the basis of the rejection.
Applicants’ discussion of dependent claims on pg 12-15 is noted but not persuasive for reasons set forth in the rejections.
Indefiniteness
Claims 1, 3-8, 10-12, 15, 27 remain and claims 47, 48 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.
A) The metes and bounds of “keratinocyte progenitor cells (KPCs)” in claims 1, 27, 48 cannot be determined. The specification and the art at the time of filing do not define KPCs. The specification contemplates “hair follicle bulge stem cells (HFBSCs)” (pg 1, para 3, and throughout the disclosure and examples). However, the “bulge” of a hair follicle is simply a location within a hair follicle. Any hair follicle stem cell can be put into the “bulge” of a hair follicle and be considered an HFBSC. Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16) taught differentiating hiPS cells into HFBSCs and implanting them into the skin of a human as required in claim 1 (abstract) but did not teach the metes and bounds of HFBSCs. Pg 34-35 discusses “Generation, Characterization, & Differentation of hiPSCs into HFBSCs” without defining the metes and bounds of HFBSCs. Expression analysis of HFBSCs involving CD200, ITGA6, ITGB1, CD63, Nanog, Oct4, is discussed (para 131-133) without clearly setting forth the structures that define HFBSCs or the function/potency of HFBSCs. The specification does not correlate the structure/function/potency of HFBSCs to any hair follicle stem cell that was well known in the art. It is unclear whether these undefined HGBSCs described by Ibrahim and applicants’ disclosure are KPCs as required in claims 1, 27, 48.
Ohyama (J. Derm. Sci. 2007, Vol. 46, No. 2, pg 81-89) taught the hair follicle bulge is a reservoir for epithelial stem cells and keratin stem cells (KSCs). Therefore, KSCs encompass well-known KSCs described by Ohyama but not epithelial stem cells.
However, the specification fails to enable those of skill to determine when they had arrived at KPCs as required in claims 1, 27, 48, specifically HGBSCs expressing CD200, ITGA6, ITGB1, CD63, KRT18, KRT19, KRT15 as shown in Fig. 1, because the specification and Ibrahim do not teach the function or potency of the stem cells or compare the structures/functions of keratinocyte progenitors that were well known in the art.
Pg 13 (para 64-66) and pg 18-28 discuss differentiation of pluripotent cells into HFBSCs without defining when KPCs have been obtained. Applicants point to Fig. 1 and 4 and paragraphs 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1.
Pg 14 (para 67-68) says the HFBSCs were characterized using antibodies that bind Oct4, P63, KRT15, KRT19, KRT8, KRT18, KRT5, and KRT14 at days 0, 11, 18, 25. These antibodies are not the same profile as those in Fig. 1. However, it is unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 14-15 (para 69-70) discusses culturing HFBSCs with mouse dermal cells but does not teach the specifics of the outcome, how/whether the HFBSCs differentiate, or the structure/function of the cells obtained from these protocols. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 34-35 discusses differentiation of iPS cells into HFBSCs and characterizing HFBSCs. Again, applicants point to Fig. 1 and 4 and 65, 66, 84-100 which are limited to specific protocols and reagents on specific days that are essential to perform the procedure but are missing from the claims. Pluripotent cells are differentiated into embryoid bodies (EBs) on days 1-6 which was well-known in the art. However, the conditions for “Plating” on days 6-10 that are essential to obtain HFBSCs on day 11 are not disclosed, and it is unclear how the HFBSCs in applicants’ examples correlate to the KPCs in claims 1, 27, 48. Fig. 1 is limited to culturing EBs in EGF, ATRA, and BMP4 which is missing from claims 1, 27, 48. Claims 1, 27, 48 encompasses using any reagents to obtain any KPCs; however, the metes and bounds of those reagents are unclear from the specification and the art. Fig. 1 is limited to obtaining cells expressing CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 which is not in claims 1, 27, 48. Claims 1, 27, 48 are not limited to obtaining cells that express CD200, ITGA6, ITGR1, KRT18, KRT19, KRT15, and p63 as shown in Fig. 1. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Figures 2 and 9 are discussed on pg 34-35, but it is unclear how the expression patterns claimed correlate to any well-known hair follicle stem cell or any newly discovered stem cell. If the cells observed are new, then applicants fail to teach the function or potency of the new cells or how they compare to well-known keratinocyte progenitors.
Pg 35-37 discusses the “Expression Dynamic of the Molecules Determining hiPSC-HFBSC fate”. Pg 35, para 137, says ITGA6, ITGB1, and CD200 are “critical for consummation of HFBSC generation”, but claim 1 does not require expression of either protein. Oct4 expression decreased and P63, KRT15, KRT19, and KRT8 expression increased (para 138, 140) which is missing from the claims. It is unclear what function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Pg 38 (para 143) characterizes keratinocytes derived from HFBSCs. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 39-42 describes “Characterization in vivo of hiPSC-HFBSCs following transplantation”. Applicants obtained hair follicles from the HFBSCs implanted into the skin of mice but only in the presence of MDCs (mouse dermal cells) (pg 41, line 3). Applicants did not obtain human hair. It is unclear how these HFBSCs correlate to any other keratinocyte progenitors as broadly encompassed by claims 1, 27, 48.
Pg 42-46 describes “Assessing the necessary & sufficient elements for HF generation”. One sentence say “all of the seven molecules (markers) required for complete HF generation were also fundamental to the earliest stages of normal development” without teaching the 7 essential markers. Fig. 1 shows 7 markers (ITGA6, ITGB, CD200, KRT15, KRT19, KRT8, and P63), but they are not in the claim. It is unclear what specific function or potency is associated with cells that express ITGA6, ITGB, CD200, KRT15, KRT19, and KRT8. It is also unclear how these HFBSCs correlate to the KPCs in claims 1, 27, 48.
Accordingly, those of skill would not be able to determine the metes and bounds of when the HFBSCs that are keratinocyte progenitors described in the specification were obtained. Nor would those of skill be able to determine the metes and bounds of keratinocyte progenitors in claims 1, 27, 48.
B) The phrase “thereby preparing the hair follicle” in the phrase “implanting the KPCs into skin of a human subject, thereby preparing the hair follicle” in claims 1, 27, 48 equivalates implanting KPCs into human skin with making a hair follicle without clearly saying a hair follicle is obtained. Merely implanting KPCs into human skin is not “making a hair follicle”. Perhaps applicants are attempting to claim functional language, i.e. ---implanting the KPCs into skin of a human subject such that a hair follicle is formed---. Or perhaps applicants are attempting to say the KPCs are implanted into an established hair follicle, i.e. “implanting the KPCs into a hair follicle of a human subject---. Regardless, the final step and, ergo, the preamble of claims 1, 27, 48 are unclear.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Claim Rejections - 35 USC § 102
Withdrawn rejection
The rejection of claims 1, 3, 11, 12, 15, 27 under 35 U.S.C. 102a1 as being anticipated by Yang (Nature Comm., 2014, Vol. 5, pg 1-11) has been withdrawn because Yang did not teach floating iPS cells in culture such that EBs form as required in claims 1, 27 as newly amended (previously in claim 6).
Pending rejection
Claims 1, 3-8, 10-12, 15, 27 remain and claims 47, 48 are rejected under 35 U.S.C. 102a1 as being anticipated by Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16).
Ibrahim taught floating iPS cells in culture such that EBs were obtained and cultured the EBs on collagen I coated plates until keratinocyte progenitors were obtained as required in claims 1, 27, 48 (pg 3, Fig. 1 caption; pg 3, col. 1, “first, the formation of embryoid bodies (EBs) in a floating culture followed, second, by plating the EBs onto collagen I coated plates”). The keratinocyte progenitors because they were “HFBSCs” that expressed CD200, ITGA6, ITGB1, KRT15,KRT18,KRT19, and P63 (pg 3, Fig. 1) described by applicants as being part of the invention. The culture process is from 16-18 days as required in claims 1, 27, 48 because Ibrahim taught “transplanting at day 16-18 of differentiation – the point at which the hiPSCs have lost potency, have attained optimal expression of HFBSC markers” (abstract).
Ibrahim taught KPCs that express CD200, ITGA6, ITGB1, KRT15,KRT18,KRT19, and P63 as required in claim 3 (pg 3, Fig. 1, HFBSCs).
iPS cells were made using the components of claim 4 (pg 2, “Generation of hiPSCs from dermal fibroblasts”).
The formation of EBs in a floating culture followed culturing on collagen I coated plates had the same timing as required in claims 6 and 48.
iPS cells were differentiated using the on collagen I coated plates (pg 3, Fig. 1 caption, Fig. 1, days 5-18; pg 3, col. 1, “first, the formation of embryoid bodies (EBs) in a floating culture followed, second, by plating the EBs onto collagen I coated plates”) as required in claims 7-8.
The protocol required using ATRA, L-AA, EGF and BMP4 as required in claim 10 was taught by Ibrahim (pg 3, Fig. 1 and caption).
The protocol in claim 11 was optional.
Implanting was intradermal (pg 4, col. 2, line 5) as required in claims 12 and 47.
The HGBSCs did not express KRT5 or KRT14 as required in claim 15 and then increased their expression days 18-25 (pg 5, col. 2, 2nd para).
Ibrahim taught all the steps of claims 27 and 48 for reasons set forth above.
Response to arguments
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Applicants argue Ibrahim did not teach differentiating iPS cells for 16-18 days as required in claims 1, 27, 48. Applicants’ argument is not persuasive. The culture process is from 16-18 days as required in claims 1, 27, 48 because Ibrahim taught “transplanting at day 16-18 of differentiation – the point at which the hiPSCs have lost potency, have attained optimal expression of HFBSC markers” (abstract).
Claim Rejections - 35 USC § 103
Withdrawn rejection
The rejection of claims 1, 3-8, 10-12, 15, 27 under 35 U.S.C. 103 as being unpatentable over Yang (Nature Comm., 2014, Vol. 5, pg 1-11) in view of Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16) has been withdrawn because Yang did not teach floating iPS cells in culture such that EBs form as required in claims 1, 27 as newly amended (previously in claim 6).
New rejection
Claims 1, 3-8, 10-12, 15, 27, 47, 48 are rejected under 35 U.S.C. 103 as being unpatentable over Yang (Nature Comm., 2014, Vol. 5, pg 1-11) in view of Ibrahim (Curr. Protocols Stem Cell Biol., 2020, Vol. 54, No. 1, e119, pg 1-16).
Yang taught making hiPS cells, differentiating the hiPS into hair follicle epithelial stem cells “required for hair follicle growth and cycling”. Yang taught implanting the hair follicle stem cells to a human as required in claim 1 (abstract).
Yang did not teach floating iPS cells in culture such that EBs form as required in claims 1, 27, 48 or making iPS cells using the components in claim 4.
However, Ibrahim taught making hiPS cells, differentiating the hiPS into hair follicle stem cells, and implanting the hair follicle stem cells to a human (abstract) as required in claim 1, 27, 48. iPS cells were made using the components of claim 4 (pg 2, “Generation of hiPSCs from dermal fibroblasts”). Ibrahim taught HFBSCs that express CD200, ITGA6, ITGB1, KRT15,KRT18,KRT19, and P63 as required in claim 3 (pg 3, Fig. 1, HFBSCs). iPS cells were made using the components of claim 4 (pg 2, “Generation of hiPSCs from dermal fibroblasts”).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to make iPS cells and differentiate them into keratinocyte progenitors as described by Yang using the means described by Ibrahim. Those of ordinary skill in the art at the time of filing would have been motivated to do so as a matter of design choice.
Ibrahim taught KPCs that express CD200, ITGA6, ITGB1, KRT15,KRT18,KRT19, and P63 as required in claim 3 (pg 3, Fig. 1, HFBSCs).
iPS cells were made using the components of claim 4 (pg 2, “Generation of hiPSCs from dermal fibroblasts”).
The formation of EBs in a floating culture followed culturing on collagen I coated plates had the same timing as required in claims 6 and 48.
iPS cells were differentiated using the on collagen I coated plates (pg 3, Fig. 1 caption, Fig. 1, days 5-18; pg 3, col. 1, “first, the formation of embryoid bodies (EBs) in a floating culture followed, second, by plating the EBs onto collagen I coated plates”) as required in claims 7-8.
The protocol required using ATRA, L-AA, EGF and BMP4 as required in claim 10 was taught by Ibrahim (pg 3, Fig. 1 and caption).
The protocol in claim 11 was optional.
Implanting was intradermal (pg 4, col. 2, line 5) as required in claims 12 and 47.
The HGBSCs did not express KRT5 or KRT14 as required in claim 15 and then increased their expression days 18-25 (pg 5, col. 2, 2nd para).
Ibrahim taught all the steps of claims 27 and 48 for reasons set forth above.Yang taught The folliculogenic epithelial stem cells of Yang inherently MUST express CD200, ITGA6, ITGB1, KRT15,KRT18,KRT19, and P63 as required in claim 3 because they were made using the exact same protocol of claim 1 and because they were made using a protocol described by applicants as being part of the invention.
Yang taught the stem did not express KRT5 or KRT14 as required in claim 15 and then increased their expression days 18-25 (pg 4, Fig. 2i).
Yang taught Yang taught all the steps of claim 27, 48 for reasons set forth above.
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
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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