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 .
DETAILED ACTION
Claim Status
Claims 1-19 are currently pending in this application.
Election/Restriction
Election was made without traverse of Group I, claims 1-9, in the reply filed Aug. 3, 2026 and of the species of neurodegenerative Alzheimer’s disease; efficacy shown by change in transcriptome; (4) neural induction media comprising DMEM-F12 with 15% (v/v) KSR, 5% (v/v) heat-inactivated FBS, 1% (v/v) Glutamax, 1% (v/v) MEM-NEAA, 100 µM β-mercaptoethanol; supplemented with 10 µM SB-431542, 100 nM LDN-193189, 2 µM XAV-939 and 50 µM Y27632; and (5) the spinning cortical organoid culture medium comprises a 1:1 mixture of DMEM-F12 and Neurobasal media, 0.5% (v/v) N2 supplement, 1% (v/v) B27 supplement without vitamin A, 0.5% (v/v) MEM-NEAA, 1% (v/v) Glutamax, 50 µM β-mercaptoethanol, 1% (v/v) penicillin/ streptomycin and 0.025% insulin. Claims 10-19 are withdrawn from further consideration as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1-9 have been considered on the merits.
Disclosure Objections
Although the use of trademarks 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.
The use in the specification of the terms “Glutamax” and “Neurobasal” as well as “B27” or “N2” supplement, refers to a trademark used in commerce and has been noted in this application, such as at [0008], [00100]-[0011], [0085], [0088]-[0089], and [0135] in the PGPub. These terms 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. Appropriate correction is required because the proprietary nature of trademarks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains references to colors within the drawings; however, the drawings lack any color. The Brief Description of the Drawings refers to green and pink circles in Fig. 3; red and blue colors in FIG. 5-6; 10-11; and blue and green in FIG. 9H Appropriate correction is required.
Claim Interpretation
In claim 1, the order of the steps a)-d) is not considered set. The MPEP (2111.01(II)) notes it is generally improper to read a specific order of steps into method claims unless, as a matter of logic or grammar, there is an implicitly required order that one step must precede a second step. The broadest reasonable interpretation of claim 1 has no implied order by either logic or grammar except for step a) preceding steps b) and c), particularly due to the ambiguity of the term “the cells” in steps b) and c) as noted in the 112(b) section below; however, it would be straightforward to expressly set the desired order of any of the method steps by amending claim 1. Of note this interpretation encompasses performing the d) inducing step before, after or during step a).
In claim 1, the “hESCs” or human epithelial cells lacking “the” inducible Pu.1 transcription factor gene are interpreted as cells not comprising the same inducible Pu.1 transcription factor gene as the “Pu.1i-hESCs” but not necessarily lacking all other inducible Pu.1 transcription factor genes.
Claim 1 recites the term “organoid,” which is noted as defined in the specification contrary to its plain and ordinary meaning at [0044] of the PGPub. Cortical organoids are a type of brain organoid known in the prior art as produced using pluripotent stem cells, not epithelial stem cells as restricted in the instant specification (see e.g., Gopalakrishnan, Bioessays 41: e1900011 (2019) at abstract, pg. 1, left col). The prior art teaches that self-organization processes of cultured pluripotent stem cells can give rise to forebrain/cortical patterning when forming into brain organoids (id. at pg. 2-4, Fig. 1; Tables 1-2). Nowhere does the instant application define “epithelial stem cell” or “human epithelial stem cell,” so these terms are given their ordinary and customary meaning in the art.
Claim Rejections - 35 USC § 112(a) - Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 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.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements that are not adequately described in the specification and that is not conventional in the art as of applicant’s effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 USPQ2d 1641,1646 (1998).
In making a determination of whether the application complies with the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is claiming and what Applicant has possession of.
The preamble of claim 1 recites “preparing a microglial cell comprising cortical organoid,” which is interpreted as breathing life into the claim with the implied limitation that performing the method produces the structure of a cortical organoid comprising at least one microglial cell because this is the apparent raison d'etre of this claim not just a statement of method effect (see MPEP 2111.02). Claim 1 also recites in step a) that two types of human epithelial stem cells are required and sufficient to perform the claimed method to produce said cortical organoid.
This scope is not supported by the written description regarding predictably producing such organoids from the full scope of human epithelial stem cell limited cell types.
The prior art teaches using human “pluripotent” stem cells (embryonic or induced) to produce brain organoids via epithelial stem cell intermediates, e.g., embryoid bodies in serum-free media or rosettes (Gopalakrishnan (2019) at pg. 2). However the prior art is silent as to starting only with “epithelial” stem cells as encompassed by the instant claims and merely culturing these epithelial stem cells in neural induction media to produce a cortical organoid, regardless of vitamin A and Pu.1 expression. Furthermore, the prior art teaches pluripotent stem cell-derived brain organoids can comprise mesodermal lineage microglial cells, whether appreciated or not at the time (Ormel et al., Nat Commun 9: 4167 (2018), IDS ref.; at abstract; see also instant pg. 37, 2).
Therefore, the written description provided by the applicant in view of prior art must describe these features missing from the prior art so that one of the ordinary skills in the art would recognize possession of these novel aspects of the claimed method, encompassing any type of human epithelial stem cell and not requiring any pluripotent stem cell, such as by providing a nexus between structure and function correlated to a working embodiment or predictability supported by or derived from empirical data not publicly available prior to the instant filing.
In analyzing whether the written description requirement is met for a genus in a claim, it is first determined whether a representative number of species have been described by their structure. In the instant case, the only cell types actually reduced to practice start as pluripotent stem cells (HES3, BC4, BC61), which are subjected to steps a)-d) of claim 1 without any hint of evidence of epithelial character until day 35 or 70, e.g., SOX2 expression with HES1 and/or VIM (FIG. 5). However, applicant is invited to show evidence to the contrary.
Nowhere does the instant specification describe any method generating a cortical organoid only from human epithelial cells. Thus, no representative species of the genus is provided beyond intermediates of pluripotent stem cells already known in the prior art. In view of the prior art, while it is predictable the method of claim produces cortical organoids comprising microglia from human pluripotent stem cells, it is unpredictable when epithelial stem cells are exclusively used throughout the entire method without pluripotent reprogramming. Furthermore, the scope of human epithelial cells encompasses various terminally differentiated, mature subtypes unrelated to cortical organoid generation, such as airway, hepatic, intestinal, mammary, renal, and retinal.
Thus, this limited descriptive information is not deemed sufficient to reasonably convey to one skilled in the art that applicant is in possession of the full scope of the method of claim 1 encompassing the broad genus of human epithelial stem cells but also encompassing methods limited solely to human epithelial stem cells and excluding pluripotent stem cells. Nothing in any of the dependent claims alters this analysis, such as by including a pluripotent stem cell or narrowing the scope of the epithelial cell. Thus, the skilled artisan could not rely upon the disclosure in the specification such that the specification would sufficiently describe that Applicant was in possession of the entire scope of the claimed method encompassed by claims 1-9.
35 USC § 112(a) – Scope of Enablement
Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while the specification is enabled for wherein human pluripotent stem cells are included in the culture for the first method steps and are converted into neuroprogenitor human epithelial stem cells; the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to prepare cortical organoids merely from human epithelial stem cells as encompassed by all the claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The claims are directed to methods of “preparing a microglial cell comprising cortical organoid” from as few as two types of human epithelial stem cells in a coculture. The claims are broad in that both no other cell type is required and the term “human epithelial stem cell” encompasses a broad genus as noted for written description above.
The state of the art:
The prior art teaches making cortical organoids from pluripotent stem cells (embryonic or induced), which can temporarily produce epithelial stem cell intermediates, e.g., embryoid bodies in serum-free media or rosettes (Gopalakrishnan (2019) at pg. 2). The prior art is silent as to starting only with “epithelial” stem cells as encompassed by the instant claims and merely culturing these epithelial stem cells in neural induction media to produce a cortical organoid; however applicant is invited to furnish evidence the contrary. Therefore, the disclosure provided by the applicant in view of prior art must encompass a wide area of knowledge to a reasonably comprehensive extent so that one of the ordinary skills in the art would be able to practice the invention without any undue or reasonable burden being on such artisan.
The amount of direction and guidance and working examples provided by Applicant:
The instant application lacks any working example of a method according to the scope of claim 1 limited to only epithelial stem cells. Instead, the instant specification shows examples only using embryonic pluripotent stem cells (HES3, BC4, BC61), which are not epithelial in nature. These human pluripotent stem cells were subjected to steps a)-d) recited in claim 1 without any hint of evidence of epithelial character until day 35 or 70, e.g., SOX2 expression with HES1 and/or VIM (FIG. 5), which is after performing all steps a)-d) and continuing step d).
From this empirical data, it not predictable in view of the art that starting with any human epithelial stem cell type would resulting in producing a cortical organoid, regardless of process details, e.g., regarding coculture conditions, vitamin A and/or Pu.1 expression. Thus, neither the instant application nor the prior art describes a method enabled over the full scope of claim 1, which is broad in the recitation of human epithelial stem cells generally and without requiring any pluripotent stem cell.
The quantity of experimentation needed to make and/or use the invention:
Extensive experimentation would be required to determine how to generate a cortical organoid solely from human epithelial stem cells generally and for all subtypes thereof without requiring any pluripotent stem cell. The science of brain organoid methods has not evolved such that, without guidance or working examples in the specification for preparing or modifying the epithelial stem cells to ensure such result, the claims lack enablement for the full scope of the claimed invention. Importantly, extensive experimentation would be required to determine how to generate cortical organoids starting solely with human epithelial cells without any pluripotent stem cells present.
In summary, the claims are rejected under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement to a person skilled in the art, to which it pertains or with which it is most nearly connected, to perform the claimed invention to predictably produce a cortical organoid over the full scope of the claims. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to the human epithelial stem cell, undue and unreasonable experimentation would have been required for one skilled in the art to use the claimed methods to prevent hearing loss over the entire scope of the claims. While no dependent claim is enabled as explained above, the claims encompass enabled subject matter in view of the prior art teaching multiple methods of generating cortical organoids using a population of pluripotent stem cells comprising a subset which pass through an epithelial cell type, such as neuroectodermal neural progenitor cells.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 1, 3, and 7-8 each recites text within parentheses, which is not clear if what is within the parentheses recites a claim limitation, optional feature, abbreviation and/or nickname. Claims 2, 4-6 and 9 are included in this rejection due to their dependence from indefinite claim 1. In particular, claim 1 recites “an inducible Pu.1 transcription factor gene (Pu.1i-hESCs)” and “the inducible Pu.1 transcription factor gene (hESCs),” which is ambiguous and unclear as to whether what is in parentheses refers to the gene or the cells comprising it based on placement. Claims 2-9 are included in this rejection due to their dependence from indefinite claim 1.
Claims 1-5 and 7-9 each recites what appears to be at least one abbreviation, if there are any abbreviations in the claim set, then the abbreviation(s) needs to be spelled out at least once, see e.g., hESCs, hESCs, DMEM-F12, MEM-NEAA, KSR, FBS, and dox. Claim 6 is included in this rejection due to its dependence from indefinite claim 1.
Claim 2 recites the phrase “at a ratio of 1:9,” which is unclear and ambiguous as to what is at this ratio, such as one cell type to another cell type, Pu.1i-hESC solution to hESC solution, and/or initial cell medium to a neural induction medium.
Claims 3, 7 and 8 each recites trademarks/trade names, such as GlutaMax®, Neurobasal® media, N-2 supplement and B27™ supplement. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademarks/trade names “Glutamax,” “Neurobasal,” “B27,” and “N2” are used to identify/describe compositions comprised within a cell culture medium, accordingly, the identification/description is indefinite.
Claims 4-6 recites “beginning on day” “2” or “4,” each of which lacks sufficient antecedent basis and is unclear and ambiguous in view of claim 1 having no definition of a start time nor a “beginning” for a day, e.g., during the co-culturing for at least 8 days, as well as both “co-culturing” and “inducing” representing potential start times of the entire method. It would be remedial to set the time counting from the moment of comingling the Pu.11-hESCs and hESCs in the neural induction medium, if this was the intent.
Claims 4 and 9 each recites the phrase “Pu.1 is inducible,” which is unclear as to what is being induced and to which “Pu.1” refers. It would be remedial to rephrase as “the Pu.1 expression is inducible” or as “the expression of the Pu.1 gene is inducible.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Xiang (Xiang et al., Cell Stem Cell 21: 383-98 (2017), IDS ref.) in view of Chen (Chen et al., Stem Cell Reports 16: 1363-80 (2021)) and Xu (Xu et al., Stem Cell Reports 16: 1923-37 (2021)).
Regarding claims 1, 3 and 7, Xiang teaches a method (pg. 385, col. 1, para. 1) of producing a human cortical organoid comprising microglia, the method comprising co-culturing human stem cells in a medium comprising DMEM-F12, 15% (v/v) knockout serum replacement (KSR), 1% (v/v) MEM-NEAA, 1% (v/v) Glutamax, 100 µM β-Mercaptoethanol, 100 nM LDN-193189, 10 µM SB431542, 2 µM XAV939, 50 µM Y-27632 compound and 5% (v/v) heat-inactivated FBS (pg. E3, para. 3) for over 8 days (e.g., 10 days), then continuing culturing human epithelial stem cells (day 10-18) in a medium lacking vitamin A with spinning agitation (orbital shaker at 80 rpm/min) (pg. e3, para. 4, Fig. 1) wherein the medium comprises a 1: 1 mixture of DMEM-F12 and Neurobasal media, supplemented with 0.5% (v/v) N2 supplement, 1% (v/v) B27 supplement without vitamin A, 1 % (v/v) Glutamax, 0.5% (v/v) MEM-NEAA, 0.025% (v/v) human insulin solution, 50 µM β-mercaptoethanol and 1 % (v/v) Penicillin/Streptomycin, and then after day 18 culturing in a medium as above but with vitamin A added (pg. e4, para. 1).
Xiang does not teach using expression of an inducible Pu.1 transcription factor gene in a subset of the stem cells of a culture (co-culture) and, thus, does not teach any Pu.1 expression inducing step during the method.
However Chen teaches directing human pluripotent stem cells in culture to becoming microglia (iMG) by forced expression of Pu.1 (SPI1) (pg. 137; abstract). Chen teaches methods of accomplishing this using an inducible recombinant Pu.1 (SPI1) transgene (Fig. 1-2). Chen also teaches a co-culture of Pu.1-induced microglia with neuronal induced human pluripotent stem cells, such as to study microglia-neuron interactions (Fig. 6; pg. 1371, last para., to 1374, 1st para.). Further, Xu teaches producing microglia containing brain organoids from co-cultures and that using cortical organoid incorporated microglial cells more accurately model human microglia functions beyond merely mono microglial cell culture (abstract). Xu teaches how to control the total number of microglia in these organoids during coculture to closely match the naturally occurring ratio in the human brain (5-10%) by adjusting the starting ratio of the two cell types of the coculture (e.g., 9 to 1) (pg. 1933; pg. 1924, left col., last para., Fig. 1-2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method of Xiang to include forced expression of Pu.1 from an inducible recombinant transgene as taught by Chen and to coculture the Pu.1 expressing cells as minority population within a larger human stem cell population to induce formation of a cortical organoid comprising a minority of microglial cells. One of ordinary skill in the art with the goal of recapitulating a more native brain tissue would be motivated Xu teaching 5-10% of cells in situ are microglia and Chen teaching inducible Pu.1 expression to drive microglia differentiation in culture. Further, one of ordinary skill in the art with the goal of studying human microglia would be motivated by Xu teaching using co-cultures to incorporate microglial cells into brain organoids to more accurately model human microglia situations (abstract).
Although Xiang teaches producing brain organoids from human embryonic stem cells and Chen teaches programming microglia from human pluripotent stem cells, the skilled artisan recognizes during differentiation in culture media these stem cells become human epithelial stem cells as neuroectodermal or neuroepithelial neural progenitor cells (e.g., SOX2+ NKX2+) when cultured in neural inducing media (e.g., comprising 100 nM LDN-193189 and 10 µM SB431542 or a combination LDN-193189, SB431542, and XAV-939) (see e.g., Xiang at pg. 384, right col., 2nd para.; Fig. 2). Thus, the claim limitation of step a) is met at some point over a cumulative culturing in medium during the entire process for any extended period of time, e.g., at least 30, 40, 45, 56, 64, 70, 71, 72, 75, or 105 days, as taught by Xiang (Fig. 1A, months).
Regarding claim 2, although neither Xiang nor Chen teaches wherein the coculture ratio of Pu.1 gene recombinant cells to normal cells is expressly 1:9, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method of taught by the combination Xiang, Chen and Xu to coculture the Pu.1 expressing cells as a 10% minority population to induce formation of a brain organoid comprising a naturally level of microglial cells. One of ordinary skill in the art would be motivated to mimic natural brain tissue as much as possible and Xu teaches 5-10% of brain cells in situ are microglia (i.e., a ratio of no more than 1 in 9 brain cells).
Regarding claim 5, Xiang teaches “removing” (not supplementing with) FBS from the neural induction medium beginning on day 2 (pg. e3 para 3).
Regarding claim 6, Xiang teaches “removing” (not including) Y-27632 in the neural induction medium beginning on day 4 (pg. e3 para 3).
Regarding claim 9, Chen teaches inducing Pu.1 expression by adding 2 µM doxycycline to a culture medium comprising cells comprising a recombinant Pu.1 (SPI1) transgene operably linked to a TetO promoter (Tet-On or pTetO) (pg. 1378, pg. 1365). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to modify the method of Xiang to include during the co-culturing forced expression of Pu.1 from an inducible recombinant transgene as taught by Chen and select a TetO promoter induced by 2 µM doxycycline in the culture medium. One of ordinary skill in the art would make this selection as the prior art had already validated and established this TetO system for the same prior art purpose.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Xiang in view of Chen and Xu as applied above, and further in view of Zaldumbide (Zaldumbide et al., Biotechnol Lett 32: 749-54 (2010), IDS ref.).
Regarding claim 4, the combination of Xiang, Chen and Xu does not expressly teach using a dox concentration of 0.5 µM to induce expression of the Pu.1 recombinant transgene, instead teaching 2 µM as noted above.
However Zaldumbide teaches 0.5 µM dox (doxycycline) is a known prior art accepted amount for induction of a TetO promoter (Tetop) controlled heterologous gene expression (pg. 752, Fig. 1-2). Thus, it would have been obvious to modify the method to wherein the doxycycline inducing concentration is 0.5 µM in the medium as disclosed by Zaldumbide as a known prior art concentration effective to induce expression.
Therefore, the claimed invention as a whole is prima facie obvious prior to the earliest effective filing date in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
