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
The amendment filed 08/20/2026 has been entered. Claims 1 – 20 remain pending and are under consideration.
Priority
This application is the U.S. national stage entry of PCT/US2021/040178 filed 07/01/2021, which claims priority to U.S. provisional patent application No. 63/047697 filed 07/02/2020.
Claim Objections
Claims 2 and 3 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 10 is objected to because of the following informalities: because claim 1 has been amended to specifically recite the small molecules listed in dependent claim 10, claim 10 should be written to limit the concentrations of those small molecules, not further include the molecules a second time. For example “wherein SB431542 is present at a concentration of…”. Appropriate correction is required.
Claim 15 is objected to because of the following informalities: because claim 1 has been amended to specifically recite the small molecules listed in dependent claim 15, claim 15 should be written to limit the concentrations of those small molecules, not further include the molecules a second time. For example “wherein SB431542 is present at a concentration of…”. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: “the culture medium” recited in line 2 should read, “the second culture medium” to be reflective of the language used in claim 1, step b. Appropriate correction is required.
Claim 19 is objected to because of the following informalities: “following withdrawal of” recited in line 2 should read, “withdrawing the” to actively recite a withdrawal step as there is no such step in claim 1 or 19. With this change, the term “and” should be inserted at line 3 prior to the term “culturing”. Appropriate correction is required.
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.
Claims 1 and 4-20 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 the claimed method wherein the human stem cells are human pluripotent stem cells (pPSCs), does not reasonably provide enablement for carrying out the claimed method wherein the human stem cells any type of human adult or embryonic stem cell. 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 and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "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 1404). 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 weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention-The nature of the invention relates to directing the differentiation of human pluripotent stem cells to generate spinal dl4 progenitor cells that are PTF1A+/PAX7+/ASCL1+, which are of a dorsal nature.
Breadth of the Claims-The claims are broad in encompassing use of any type of stem cells as a starting cell, including hematopoietic stem cells, neural stem cells, satellite cells, dental pulp stem cells, melanocyte stem cells, mesenchymal stem cells etc.
State of the Art-The art at the time of filing held that human adults and embryos comprise numerous stem cell types of differing fate potential. Hook (August 2020, Drug Discovery world, https://www.ddw-online.com/stem-cell-differentiation-1117-202008/; pdf attached) teaches that pluripotent stem cells are capable, when given the appropriate spatial and temporal signals, of becoming any type of cell in the body. Other stem cell types have restricted potential and are not capable of giving rise to any cell type. These other stem cell types are generally capable of giving rise to the tissue from which they were isolated. These stem cell types are successively limited through their differentiation to become specific types of differentiate cells.
With specific regard to neuronal differentiation, Konstantinides (Development (2020) 147, dev193631. doi:10.1242/dev.19363) discusses that the nature of the factors the stem cells are exposed to and the order in which they are expressed or presented are fundamental in determining the differentiated cell type. Konstantinides supports that once fated for a non-neuronal cell type, different factors are needed to reroute the cells along the neuronal fate path. Cells must pass through certain intermediate phases that can affect the differentiated or mature phenotype. Konstantinides does teach that two cell types can achieve the same phenotype but the developmental paths are different and use different regulators and the resulting cells are not necessarily equivalents. It is stated, “They will have followed alternative routes during their differentiation and this will undoubtedly have had consequences on their regulatory landscapes. Although these consequences may not be immediately clear from the specific markers that are tested at the end of the differentiation protocol, it is essential to understand them if these cells are to be used as a therapeutic resource.”
Xu (2014, PLoSONE9(8): e105216.doi:10.1371/journal.pone.0105216) discusses the concepts of differentiation, dedifferentiation and transdifferentiation. “Lineage reprogramming is a new regenerative method to convert a matured cell into another cell including direct transdifferentiation without undergoing a pluripotent cell state and indirect transdifferentiation with an initial dedifferentiation-reversion (reprogramming) to a pluripotent cell state. “ (Abstract) Thus, the level of differentiation that has already occurred must be undone or changed.
As a whole, the art teaches that studies that uncover the temporal cues and fate paths needed to direct the differentiation of pluripotent stem cells to obtain a desired cell type do not correlate to stem cells of a more restricted fate. Both Konstantinideds and Xu discuss epigentic changes that occur in the genome as differentiation proceeds and that pluripotent stem cells has a more naïve epigenetic state that does not need to be reset.
Guidance in the Specification -The guidance in the specification provides teachings relating to successive differentiation of pluripotent stems, first to become spinal neurepithelial progenitors and then to spinal dl4 progenitor cells. The specification does not teach how to obtain spinal neurepithelial progenitors from any other cell type, such as hematopoietic stem cells which are restricted to become cells of the blood lineage. Likewise, other intermediate progenitor cell types are not taught to become the claimed spinal dl4 progenitors.
Amount of Experimentation-It would require an undue amount of experimentation to determine how to undo the restricted fate path of stem cell types that are not pluripotent. The skilled artisan would be required to determine how to undo or change the differentiation that has already occur in non-pluripotent stem cells in a manner that when carrying out the claimed methodology with defined combinations of factors leads to the desired spinal dl4 pogenitor cells. Accordingly, in Applicant’s remarks dated 08/20/2026, it is pointed out that use of purmorphamine, which is an activator of SHH signaling, in place of the claimed cyclopamine, leads to spinal progenitor cells of a ventral fate rather than a dorsal fate (see page 7, Section C). . Thus, the specification is only enabling for carrying out the claimed method to obtain spinal dl4 progenitors with pluripotent stem cells as a starting cell type.
Claim Rejections - 35 USC § 103
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 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.
14. The rejection of claim(s) 1 – 20 under 35 U.S.C. 103 as being unpatentable over Chen (CN-109554342-A; Filed 10/23/2018; Published 04/02/2019; previously cited), hereinafter Chen in view of Du (Du, Zhong-Wei, et al. Nature communications 6.1 (2015): 6626; previously cited), which is cited on the IDS filed 04/14/2023 in view of Ogura (Ogura, Takenori, et al. Development 145.16 (2018): dev162214.), hereinafter Ogura in view of Glasgow (Glasgow, Stacey M., et al. (2005): 5461-5469.), hereinafter Glasgow is withdrawn in light of the amendments to the claims and Applicant’s Remarks. Applicant argues that the use of cyclopamine in Du is shown, as a control (SHH antagonist in place of SHH agonist PUR), to lead to cells that do not express ventral markers but does not disclose the amount that would be necessary to obtain dorsal spinal dl4 progenitors that express PTF1, PAX7 and ASCL1, or that these dorsal markers were even expressed. Substitution of purmorphamine with cyclopamine was shown only to result in a population devoid of ventral OLIG+-expressing motor neurons and does not predictably or even necessarily, lead to the claimed spinal dI4+ progenitors (interneurons from the developing dorsal spinal cord).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
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/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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