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 .
Claim Status
Claims 5-9, 11, 13, 16-17, and 20-25 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group III, claims 5-9, 12-17, and 19, in the reply filed on Nov. 6, 2025 is acknowledged. In view of the claim amendments, none of the current claims are withdrawn and, thus, all of claims 5-9, 11, 13, 16-17, and 20-25 have been considered on the merits.
Specification
The disclosure is objected to because of the following informalities:
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 “Matrigel,” “STEMCELL Technologies,” “Lonza,” “Thermo Fisher,” “Invitrogen,” “PromoCELL,” “Panasonic,” “Selleck,” “Tocris,” “Alexa,” “Alexa Fluoro,” “Axion Biosystems,” “SIGMA-ALDRICH,” “VWR,” “SPECTRAMAX,” and “CyQuant” each of which is a trademark 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. Appropriate correction at numerous instances in the specification 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 specification appears to contain typographical errors misspelling “SB525334 as SB5253334 at least instances on pg. 6-7. Appropriate correction is requested.
Claim Objections
Claims 6-7, 20 and 23 are objected to because of the following informalities: There are numerous instances of a numeral followed by a unit (e.g., µM, nM) without a blank space between them, such as in “5µM” and “12µM” etc. Appropriate correction is required.
Claim Interpretation
In the claims, both the “cell induction medium” and “sensory neuron cell medium” are interpreted as being aqueous media based on comprising 50% (v/v) DMEM and 50% (v/v) neural basal medium.
In the claims, the term “glycine-glutamine” is considered to mean the dipeptide glycyl-l-glutamine and, thus, a concentration of “glycine-glutamine” is based on its molecular weight of about 221 g/mol (with constituents glycine being about 75 g/mol and glutamine being about 146 g/mol).
In claim 5 or 9, the phrase “55 nM-25 µM LY2157299, RepSox, SB5253334 or TEW7179” means one of LY2157299, RepSox, SB5253334, and TEW7179 in the alternative at a concentration of 55 nM to 25 µM.
In claim 8, it is noted that although the medium is limited to media comprising a serum replacement, this does not exclude media comprising a serum as well.
Claim 13 is interpreted as requiring an implied method step before step 1) of preparing the pluripotent stem cells from somatic cells using a reprogramming medium.
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 9, 13, 16-17, and 24-25 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.
M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.”
In the instant case, the claims broadly comprises a genus of concentrations and choices from among one or any combination of RepSox, SB5253334, and TEW7179. In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described.
55 nM to 25 µM of RepSox, SB5253334 or TEW7179
Claims 9, 13, 16-17, and 24-25 encompass wherein the LY2157299, RepSox, SB5253334, or TEW7179 is present in the medium within the concentration range of 55 nM to 25 µM; however, the broad scope of this concentration range does not ensure that performing the claimed methods results in differentiation of pluripotent stem cells into sensory neurons or even sensory nerve precursor cells in view of the instant application and the prior art as explained below.
Applicant has not adequately shown possession of the full scope of concentration ranges to predictably induce differentiation into sensory neurons. The working examples only show wherein the RepSox is at 5 µM, the SB5253334 is at 5 µM, or the TEW7179 is at 5 µM. Furthermore, the prior art teaches RepSox inhibition saturates at concentrations of about 80-200 nM (based on IC50 of 20 nM), SB5253334 (SB525334) inhibition saturates at concentrations of about 0.8-2 µM (based on IC50 of around 200 nM), and TEW7179 (EW7179) has a biological effect on cells at 1 nM with an IC50 of about 10-30 nM in cells regarding Smad3 (see e.g., Ide et al., Exp Dermatol 26: 1139-43 (2017) at pg. 1141, left col., Fig. 1, para. 6-7; Arai et al., PLoS One 11: e0162394 (2016) at abstract; Son et al. Mol Cancer Ther 13: 1704-16 (2014) at Fig. 1, pg. OF5, right col., 1st para.). Thus, the working examples are based on complete inhibition and going to lower concentrations below saturated threshold (about 150 nM for RepSox or 1 µM for SB525334) is not predictably having the same effect.
Thus, the single concentration species is not representative of the broad range claimed when there is no clear nexus for other concentrations as low as 55 nM for RepSox, SB5253334 or TEW7179 (which encompasses a 90-fold reduced concentration from the working examples at 5 µM).
In view of the instant data, the applicant clearly possessed a method based on the single species of LY2157299 over a concentration range of 55 nM to 25 µM. However the alternative species to LY2157299 adequately described only RepSox at 5 µM, SB5253334 at 5 µM, and TEW7179 at 5 µM, which is not representative of the range of 55 nM to 25 µM. Thusly, applicant has not adequately shown possession of the full scope of concentrations for these components to predictably induce differentiation into sensory nerve precursor cells and later into sensory neurons.
Thus, there is a lack of evidence in the instant specification as filed and in view of the prior art that applicant was in possession of the claimed methods over the full scope of concentrations and alternative components because the skilled artisan cannot envision methods wherein there is no LY2157299 and one or more of the RepSox, SB5253334 and/or TEW7179 is included at concentrations far below 5 µM, depending on the agent.
35 USC § 112(a), Scope of Enablement
Claims 9, 13, 16-17, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not enable any person, skilled in the art to which it pertains or with which it is most nearly connected to, to make/use the claimed invention over the entire scope of the claims. However the instant application in view of the prior art does enable methods for differentiating pluripotent stem cells into sensory neurons using a culture medium lacking LY2157299 at a concentration of at least 55 nM so long as at least one of RepSox, SB525334, and TEW7179 is present at about 5 µM.
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.
Breadth of the claims:
The claims are directed to methods of differentiating pluripotent stem cells into sensory nerve precursor cells and subsequently into sensory neurons with a broad scope in view of the concentration limits for RepSox, SB5253334, or TEW7179.
The state of the art:
The prior art teaches methods of promoting neuronal differentiation of pluripotent stem cells (iPSC) using a basal medium comprising DMEM/F12, N2, Knockout Serum Replacement, glutamine at 1 mM, LDN193189 at 100 nM, and optionally 10 µM SU5402, 10 µM DAPT, and 3 µM CHIR99021 (Chambers et al., Nat Biotechnol 30: 715-20 (2012) at Online Methods, left col., para. 1-2). The prior art also teaches methods of specifically generating sensory neuron cells from iPSC using a medium comprising equal parts DMEM/F12 and Neurobasal medium, N2, B27, glutamine (GlutaMAX), and NT-3 (Nickolls et al., Cell Rep 30: 932-46 (2015), IDS ref.; at pg. E4, 3rd para.).
The prior art teaches RepSox (25 µM) causes expression of neural marker S100b in embryonic stem cells (Larsen, Graduate Dissertation, 2013 at Abstract; Fig. 9 and 13), and media comprising SB525334 (1 µM) or LDN193189 (100 nM) causes pluripotent stem cells to differentiate into neurons in vitro (Fjodorova et al., Neuronal Signal. 4(2):NS20200004 (2020) at Fig. 1; pg.2, “Cell culture”; abstract).
However the prior art does not expressly teach a method, or medium used therein, for differentiating any pluripotent stem cells into sensory neuron cells or sensory nerve precursor cells using an induction medium comprising RepSox, SB5253334, or TEW7179 and all the other components recited in claim 5 or using the sensory neuron cell medium recited in claim 9. Thus, these aspects regarding the components’ concentrations and combinations must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such an artisan.
The working examples only show wherein the medium comprises RepSox at 5 µM, SB5253334 at 5 µM, or TEW7179 at 5 µM. Therefore the claims allowing wherein the RepSox, SB5253334, or TEW7179 is present in the induction medium within the concentration range of 55 nM to 25 µM is overbroad for each of these three factors in view of the evidence.
It is highly unpredictable as shown in the instant application what concentration ranges of different media components are helpful or instead too cytotoxicity or lacking any apparent effect (instant Examples and FIG. 10-13, see e.g., LDN193189 over 180 nM or below 12 nM; N2 over 2.2% or less than 0.2%; GS21 over 3.1% or less than 0.2%; glycine-glutamine over 22 mM; LY2157299 below 55 nM). The instant application fails to provide sufficient guidance to achieved the claimed outcome over the entire scope of the concentration range claimed and it would require undue and unreasonable experimentation to establish at diluted concentrations approaching 50 nM for RepSox, SB5253334, or TEW7179, which may never have the desired effect at such diluted concentrations.
Thus, there is no evidence in the instant application or the prior art that the full scope of encompassed by the claims could predictably provide the required function(s) to accomplish sensory nerve precursor cell induction and sensory neuron production. 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 reliably generate sensory neurons using the claimed methods or media. Given the lack of working examples, the lack of guidance in the prior art, and the broad scope of the claims, undue and/or unreasonable experimentation would have been required for one skilled in the art to produce the desired result over the full scope of the claims.
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 5-9, 11, 13, 16-17, and 20-25 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.
The claims are interpreted as presented in a previous section.
Claims 5 and 9 each recites a medium comprising DMEM at 50% (v/v), a neural basal medium at 50%(v/v), N2 at 0.5-2% (v/v), and GS21 or B27 supplement at 0.2-3.1% (v/v), which is incoherent and unclear as to how the total volume can be over 100% (50+50+0.5-2%+0.2-3.1% = 100.7-105.1%). Similarly for dependent claims 6-7 and 20, with narrower amounts but totals still greater than 100%. Claims 8, 11, 13, 16-17, and 21-25 are included in this rejection for depending from an indefinite claim.
Claims 5-7 and 9 each recites a medium comprising glycine-glutamine monohydrate, which is incoherent and unclear as to how a monohydrate form is maintained in an aqueous medium.
Claims 5-7 and 20 each recites a medium comprising LDN-193189 2HCl, which indicates a coordinate salt form LDN-193189 with two HCl, but which is incoherent and unclear as to how this form can remain in this form in an aqueous medium.
Claims 5-6, 9 and 20 each recites the term “SB5253334,” which is neither defined in the claims, specification or the prior art. Thus, a person skilled in the art would not understands the metes and bounds of “SB5253334” and may even confuse this term with SB525334. Claims 7-8, 11, 13, 16-17, and 21-25 are included for depending from an indefinite claim.
Claims 5-7 and 9 each recites the trademark/trade name “DMEM.” 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 name DMEM is used to identify/describe a specific cell culture medium defined by the components within and their concentrations or relative abundance. Claims 8, 11, 13, 16-17, and 20-25 are included in this rejection for depending from an indefinite claim.
Claims 5-6 and 20 recites the trademarks/trade names “B27” and “GS21” to describe a component of a medium, which are each indefinite. Claims 7-9, 11, 13, 16-17, and 21-25 are included in this rejection for depending from an indefinite claim.
Claims 9, 11, and 23 recites the term “human-NT3”, which is neither defined in the claim nor the specification and is not taught in the prior art. Thus, a person skilled in the art would not understands the metes and bounds of “human-NT3” with regard to a medium component. Claims 13, 16, and 17 are included in this rejection for depending from indefinite claim 11.
Claim 20 and 23 each recites a series of limitations with the phraseology of “X” is a percentage or concentration, e.g., “the N2 supplement is 0.7%” etc., which is ambiguous, incoherent and unclear as to how the component is a %(v/v) nM or µM and how this relates to the medium. For purposes of examination, the phraseology of “X” is a percentage or concentration is interpreted as meaning the medium comprises ‘X’ at that percentage or concentration.
In claim 22, the serum replacement is limited to “in a purified form,” which is incoherent and unclear as the claim is directed to a medium comprising many components including said serum replacement, and thus nothing about the medium is a “purified form” of any serum replacement. Note, claims 5 and 8 are directed to a medium limited by the transitional phrase comprising, which is open-ended as to other components not recited in the claims.
Claim 24 recites the trademarks/trade names “Matrigel,” “STEMCELL” and “STEMCELL Technologies,” to describe a component of a preparation, which are each indefinite. Furthermore, claim 24 recites “Matrigel (STEMCELL Technologies), which is ambiguous and unclear as to whether what is in parenthesis is a limitation or optional.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638