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 .
1. Claims 1 – 18 are pending and under consideration.
Priority
2. This application claims domestic benefit to application PCT/JP2023/005094 filed 02/15/2023 and foreign priority to application JP 2022-022101 filed 02/16/2022.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 04/03/2026 and 08/06/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
4. The drawings filed 08/06/2024 are acknowledged.
Specification
5. The abstract of the disclosure is objected to because the “[Summary]”, “[Solution]”, and “[Selected Drawing] none” should be deleted. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
6. The use of the term iMatrix, TrypLE, Matrigel, StemFit, TeSR, Essential 8, Cellmatrix, Dispase, Accutase, ReLeSR, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112
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.
7. Claims 5 and 14 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.
Claims 5 and 14 recite “the culture substrate is laminin or a fragment thereof”. The broadest reasonable interpretation of “or a fragment thereof” includes any fragment of laminin as a culture substrate that the non-detached cell does not detach from when treated with a cell detaching agent. Thus, claims 5 and 14 are genus claims that encompass any fragment of laminin. However, the instant specification fails to describe the entire genus of laminin fragments. The genus for laminin fragments is highly variant, inclusive to any amino acid or peptide derived from laminin. Thus, the genus of laminin fragments, which, when used as claimed, lacks a written description, and as such, there is no indication that Applicants had possession of the claimed invention.
From the specification, it is clear that Applicants have possession of laminin 511 and the fragment laminin 511E8 (iMatrix) (page 8, para. 3; Figure 3; para. 0030; page 16, para. 0030; page 26, para. 0049; page 30, para. 0059; page 32, para. 0060; page 47, para. 0089; page 56, para. 0106). However, claims 5 and 14 are not limited to laminin 511E18. Applicant’s specification discloses laminin 511 is a heterotrimer consisting of three subunit chains and laminin 511 means laminin in which the α chain is α5, the β chain is β1, and the γ chain is γ1 (para. 0030). Applicant’s specification discloses that laminin and its fragments are preferably those that exhibit a binding activity with integrin α6B1 with a dissociation constant of 10 nM or less (page 16, para. 0030), but does not teach which chains of laminin or specific sequences of laminin that are responsible for this binding activity. The specification fails to teach or describe any other laminin fragment apart from laminin 511E8.
The specification lacks sufficient variety of species of laminin fragments to reflect the variance in the genus since the specification provides only one example of laminin fragment (laminin 511E8). The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claim recites a broad genus of laminin fragments, with respect to all of the potential species of laminin fragments that may be culture substrates from which the non-detached cell does not detach from. The possible variations of fragments are limitless with potentially thousands of fragments that may be a culture substrate from which the non-detached cell does not detach from. The purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed by them. A patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that the inventor invented the claimed invention. Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention."
In the instant case, the breadth of the genus of laminin fragments, lacks a written description. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the specification is that the laminin fragment exhibit a binding activity with integrin α6B1 with a dissociation constant of 10 nM or less (page 16, para. 0030). However, there is no disclosure of any particular sequence of laminin that is responsible for this binding activity. The skilled artisan cannot envision the structure of all of the laminin fragments that are encompassed by the claim, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the recited genus of laminin fragments. Thus, the written description requirement has not been satisfied.
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.
8. Claims 1 – 18 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.
9. Regarding claim 1, it is unclear how a non-detached cell is used for inducing differentiation to an epidermal keratinocyte in line 3. It is unclear if the non-detached cell is the pluripotent stem cell or a different cell that is differentiated from the pluripotent stem cell, which is then differentiated to an epidermal keratinocyte or the non-detached cell is an epidermal keratinocyte. Claims 2 – 9 and 12 – 18 are also rejected as they depend from claim 1 and do not clarify the grounds of rejection.
10. Claim 2 recites the limitation "after seeding the pluripotent stem cell" in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite a step of seeding. Claim 12 is also rejected as it depends from claim 2 and does not clarify the grounds of rejection.
11. Regarding claim 4, it is unclear if “the cell” in line 4 is “the non-detached cell” or “a pluripotent stem cell” of claim 1 or a pluripotent stem cell that has undergone “inducing differentiation”.
12. Regarding claim 5, it is unclear if “the cell” in line 4 is “the non-detached cell” or “a pluripotent stem cell” of claim 1 or a pluripotent stem cell that has undergone “inducing differentiation”.
13. Regarding claim 6, it is unclear what “based on detached cells means”. It is unclear if “detached cells” refers to the pluripotent stem cells or an intermediate cell formed during “inducing differentiation”. Further, it is unclear when “performing detachment treatment” occurs during the culturing (at any point during differentiation or after a specific time under specific inducing conditions).
14. Claim 7 recites the limitation "is used for the next culture" in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite a second culturing. Claim 1 recites “inducing differentiation” and “the epidermal keratinocyte is applied”.
15. Regarding claim 10, it is unclear how a non-detached cell is used for inducing differentiation to an epidermal keratinocyte. It is unclear if the non-detached cell is the pluripotent stem cell or a different cell that is differentiated from the pluripotent stem cell, which is then differentiated to an epidermal keratinocyte. Claim 11 is also rejected as it depends from claim 10 and does not clarify the grounds of rejection.
16. Regarding claim 11, it is unclear how an epidermal keratinocyte is used to produce a three-dimensional cultured skin model because no active method steps are recited.
17. Regarding claim 13, it is unclear if “the cell” in line 4 is “the non-detached cell” or “a pluripotent stem cell” of claim 1 or a pluripotent stem cell that has undergone “inducing differentiation”.
18. Regarding claim 14, it is unclear if “the cell” in line 4 is “the non-detached cell” or “a pluripotent stem cell” of claim 1 or a pluripotent stem cell that has undergone “inducing differentiation”.
19. Regarding claim 15, it is unclear what “based on detached cells means”. It is unclear if “detached cells” refers to the pluripotent stem cells or an intermediate cell formed during “inducing differentiation”. Further, it is unclear when “performing detachment treatment” occurs during the culturing (at any point during differentiation or after a specific time under specific inducing conditions).
20. Claim 16 recites the limitation "is used for the next culture" in line 3. There is insufficient antecedent basis for this limitation in the claim because claim 1 does not recite a second culturing. Claim 1 recites “inducing differentiation” and “the epidermal keratinocyte is applied”.
Claim Interpretation
21. For the purpose of applying prior art, claims 1 and 10 are interpreted as a method of differentiating pluripotent stem cells to epidermal keratinocytes comprising differential trypsinization where “non-detached cell” is interpreted as a keratinocyte based on Applicant’s Figure 1 and Applicant’s specification at para. 0093 – 0096 and 0104. The “wherein” clause of claim 1 is interpreted as a contingent limitation (MPEP 2111.04 (II)) as claim 1 does not require an active method step of applying the epidermal keratinocyte to a three-dimensional cultured skin model.
22. For the purpose of applying prior art, claim 2 is interpreted as seeding pluripotent stem cells onto tissue culture plates coated with a cell culture substrate, and inducing differentiation 3 to 6 days later based on Applicant’s specification at para. 0032 and 0093 and Figure 1.
23. For the purpose of applying prior art, claims 4 and 13 are interpreted as the epidermal keratinocyte (non-detached cell) is obtained by seeding the pluripotent stem cell on a tissue culture plate coated with a cell culture substrate, followed by differentiation to the epidermal keratinocyte, followed by treating with the cell detaching agent based on Applicant’s specification at para. 0032 and 0093 and Figure 1.
24. For the purpose of applying prior art, claims 5 and 14 are interpreted as the epidermal keratinocyte (non-detached cell) is obtained by seeding the pluripotent stem cell on a tissue culture plate coated with laminin or a laminin fragment, followed by differentiation to the epidermal keratinocyte, followed by treating with the cell detaching agent based on Applicant’s specification at para. 0032 and 0093 and Figure 1.
25. For the purpose of applying prior art, claims 6 and 15 are interpreted as the epidermal keratinocyte is detached with a cell detaching agent based on Figure 1.
26. For the purpose of applying prior art, claims 7 and 16 are interpreted as the epidermal keratinocytes are further cultured based on Figure 1.
27. For the purpose of applying prior art, “artificial pluripotent stem cell” of claims 8, 9, 17, and 18 are interpreted as induced pluripotent cells (iPS) based on Applicant’s specification at para. 0023.
28. For the purpose of applying prior art, “derived from epidermal keratinocytes” of claims 9 and 18 is interpreted as a product-by-process limitation (see MPEP 2113) where the claims are not limited to the derivation of iPSCs from epidermal keratinocytes, but are limited to induced pluripotent cells.
29. For the purpose of applying prior art, claim 11 is interpreted as three-dimensional culturing of epidermal keratinocytes based on Figure 1.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
30. Claim(s) 1 – 9 and 12 – 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Baldeschi (US-20230081733-A1; Filed 03/02/2021; Published 03/16/2023), hereinafter Baldeschi.
Claim 1 recites a method for inducing differentiation from a pluripotent stem cell to an epidermal keratinocyte, comprising: inducing differentiation using a non-detached cell that remains after treating a pluripotent stem cell with a cell detaching agent to obtain an epidermal keratinocyte,
wherein a multi-layered horny cell layer is obtained when the epidermal keratinocyte is applied to a three-dimensional cultured skin model.
Regarding claim 1, Baldeschi teaches a method of inducing differentiation from pluripotent stem cells to epidermal keratinocytes by inducing differentiation of hESCs (“pluripotent stem cell”) with BMP-4 and trans retinoic acid (“inducing differentiation”) where the cells are treated with trypsin (“cell detaching agent”) to remove contaminant cells and the cells that remain (“non-detached cell”) are amplified (page 9, para. 0137 – 0139; Figure 1). Baldeschi teaches the method for preparing keratinocytes comprises (a) culturing pluripotent stem cells on a cell culture surface coated with a protein matrix to support cell attachment and growth in the presence of a defined human pluripotent stem cell medium; (b) culturing the adherent pluripotent stem cells on a cell culture surface coated with a protein matrix in the presence of a defined keratinocyte culture medium comprising retinoic acid and BMP-4 to generate keratinocyte progenitors for a time period of 5 to 8 days; (c) culturing the keratinocyte progenitors on a cell culture surface coated with a defined protein matrix coating in the presence of a defined keratinocyte culture medium devoid of retinoic acid and BMP-4 for a time period of 8 to 25 days; (d) treating the population of cells obtained in step c) to remove the non-adherent cells and non-conform cells and to obtained an homogeneous population of keratinocytes (page 5, para. 0070 – 0076). Baldeschi teaches cells are isolated and purified with differential trypsinization (page 8, para. 0127). Baldeschi teaches the method for preparing keratinocytes comprising more than 95, 96, 97, 98, 99% of K5+/K14+ keratinocytes further comprises (e) culturing the detached cells of step d) corresponding to the keratinocyte progenitors and/or the keratinocytes in the presence of a culture medium (page 5, para. 0082 – 0084).
Baldeschi teaches the method allows the preparation of iPSC- or ES-derived keratinocytes that provide a homogenous and pure population of keratinocytes (page 9, para. 0142). Baldeschi teaches “population of keratinocytes” refers to a population of cells that is able to reconstruct a human epidermis and that is characterized by the capacity to produce keratins in the process of differentiating into the dead and fully keratinized cells of the stratum corneum (“horny layer”) (page 2, para. 0018). Baldeschi teaches applying the keratinocytes derived from human pluripotent stem cells on polycarbonate culture inserts and culturing for stratification to produce an organotypic culture where organotypic culture refers to a three-dimensional tissue culture (page 10, left col. para. 0145; page 2, 0020; page 6, para. 0103).
Regarding claim 2, Baldeschi teaches seeding hESCs into dishes coated with L7 matrix at day 0 followed by initiating differentiation with two pulses of retinoic acid and BMP-4 at day 1 and day 5 until day 6 (“is initiated 3 to 6 days after seeding”) (page 8, para. 0127; Figure 1).
Regarding claim 3 and 12, Baldeschi teaches trypsin (page 9, para. 0139; page 5, para. 0073 and 0079).
Regarding claim 4 and 13, Baldeschi teaches the non-detached keratinocytes are obtained by (a) seeding pluripotent stem cells on a cell culture surface coated with a protein matrix (“treating a surface of cell culture equipment with a culture substrate, then seeding”) to support cell attachment and growth; (b) culturing the adherent pluripotent stem cells on a cell culture surface coated with a protein matrix in the presence of a defined keratinocyte culture medium comprising retinoic acid and BMP-4 to generate keratinocyte progenitors for a time period of 5 to 8 days; (c) culturing the keratinocyte progenitors on a cell culture surface coated with a defined protein matrix coating in the presence of a defined keratinocyte culture medium devoid of retinoic acid and BMP-4 for a time period of 8 to 25 days; (“culturing the cell using the cell culture equipment”) (d) treating the population of cells obtained in step c) to remove the non-adherent cells and non-conform cells and to obtained an homogeneous population of keratinocytes (“treating the cell culture equipment with the cell detaching agent”) (page 5, para. 0070 – 0076). Baldeschi teaches cells are isolated and purified with differential trypsinization (“treating the cell culture equipment with the cell detaching agent”) (page 8, para. 0127).
Regarding claims 5 and 14, Baldeschi teaches the non-detached keratinocytes are obtained by (a) seeding pluripotent stem cells on a cell culture surface coated with a protein matrix (“treating a surface of cell culture equipment with a culture substrate, then seeding”) to support cell attachment and growth; (b) culturing the adherent pluripotent stem cells on a cell culture surface coated with a protein matrix in the presence of a defined keratinocyte culture medium comprising retinoic acid and BMP-4 to generate keratinocyte progenitors for a time period of 5 to 8 days; (c) culturing the keratinocyte progenitors on a cell culture surface coated with a defined protein matrix coating in the presence of a defined keratinocyte culture medium devoid of retinoic acid and BMP-4 for a time period of 8 to 25 days; (“culturing the cell using the cell culture equipment”) (d) treating the population of cells obtained in step c) to remove the non-adherent cells and non-conform cells and to obtained an homogeneous population of keratinocytes (“treating the cell culture equipment with the cell detaching agent”) (page 5, para. 0070 – 0076). Baldeschi teaches cells are isolated and purified with differential trypsinization (“treating the cell culture equipment with the cell detaching agent”) (page 8, para. 0127). Baldeschi teaches the protein matrix may be laminin (“laminin”) (page 4, para. 0050).
Regarding claim 6 and 15, Baldeschi teaches differential trypsinization where cells are first treated with trypsin for 2 – 3 minutes at 37 C to eliminate contaminant cells followed by discarding the trypsin and treating with new trypsin for 5 to 10 minutes at 37 C, and the harvested cells are amplified on a protein matrix until cell banking (page 9, para. 0139; page 5, para. 0082 – 00086).
Regarding claim 7 and 16, Baldeschi teaches culturing the non-detached cells on collagen coated dishes until cell banking (page 9, para. 0139). Baldeschi teaches the method for preparing keratinocytes comprising more than 95, 96, 97, 98, 99% of K5+/K14+ keratinocytes further comprises (e) culturing the detached cells of step d) corresponding to the keratinocyte progenitors and/or the keratinocytes in the presence of a culture medium (page 5, para. 0082 – 0084).
Regarding claims 8, 9, 17, and 18, Baldeschi teaches the method allows the preparation of iPSC-derived keratinocytes that provide a homogenous and pure population of keratinocytes (page 9, para. 0142; Figure 1; page 1, para. 0005 and 0011; page 3, para. 0037 – 0038).
Therefore, Baldeschi anticipates claims 1 – 9 and 12 – 18.
31. Claim(s) 10 and 11 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Baldeschi (US-20230081733-A1; Filed 03/02/2021; Published 03/16/2023), hereinafter Baldeschi.
Claim 10 recites a method for producing an epidermal keratinocyte, comprising a step of inducing differentiation from a pluripotent stem cell to an epidermal keratinocyte using a non-detached cell after being treated with a cell detaching agent.
Claim 11 recites a method for producing a three-dimensional cultured skin model using an
epidermal keratinocyte obtained by the method for producing an epidermal keratinocyte
according to claim 10.
Regarding claim 10, Baldeschi teaches a method of producing epidermal keratinocytes by inducing differentiation of pluripotent stem cells (“pluripotent stem cell”) with BMP-4 and trans retinoic acid (“inducing differentiation”) where the cells are treated with trypsin (“cell detaching agent”) to remove contaminant cells and the cells that remain (“non-detached cell”) are amplified (page 9, para. 0137 – 0139; Figure 1). Baldeschi teaches the method allow the preparation of iPSC- or ES-derived keratinocytes that provide a homogenous and pure population of keratinocytes (page 9, para. 0142).
Regarding claim 11, Baldeschi teaches the method allow the preparation of iPSC- or ES-derived keratinocytes that provide a homogenous and pure population of keratinocytes (page 9, para. 0142). Baldeschi teaches applying the keratinocytes derived from human pluripotent stem cells on polycarbonate culture inserts and culturing for stratification (page 10, left col. para. 0145).
Therefore, Baldeschi anticipates claims 10 and 11.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZANNA M BEHARRY whose telephone number is (571)270-0411. The examiner can normally be reached Monday - Friday 8:45 am - 5:45 pm.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632
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