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 .
This application is now under examination by Examiner Valarie Bertoglio, AU 1632.
Claims 1,3,4,7, and 16-17 are under consideration.
Election/Restrictions
Applicant's election of Group I, drawn to a method of preparing reprogrammed cells, and the species of Oct4 (claim 2) and mesenchymal tissues and parenchymal tissues containing primary fibroblasts (claim 4), in the reply filed on 11/15/2023 stands.
Specification
The specification at page 19, lines 11-12 reads, “…stem cells of the present disclosure also do show any endogenous expression…”. It is not clear if that sentence was intended to read “…stem cells of the present disclosure also do not show any endogenous expression…” or “…stem cells of the present disclosure also show endogenous expression…”.
Claim Objections
Claim 4 is objected to because of the following informalities: it appears the last word in the claim should be “cells” not “tissues”. 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 1,3,4,7, and 16-17 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 an in vitro method of reprogramming bat cells using the claimed method steps wherein the cells take on an altered morphology, have increased doubling capacity and are more susceptible to Henipavirus infection, does not reasonably provide enablement for reprogramming any species of cells into stem cells exhibiting any stem cell characteristics. 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).
The invention relates to altering the ‘differentiation state’ of a cell. The claims broadly require a mammalian somatic cell be reprogrammed to a stem cell using nucleic acids encoding ESRRB, CDX-2 and c-MYC (ECM). The claims are broad with regard to the mammal species and the ‘phenotype’ of a stem cell.
The specification teaches reprogramming bat somatic cells using ECM. Tracheal and lung cells that express exogenous ECM show altered morphology, live longer in culture and have a higher infectivity rate by Nipah Virus (NiV). The specification also teaches introducing nucleic acids encoding ECM into bovine, human, porcine and equine cells. The specification only teaches that these cells show “major morphological changes”.
The specification teaches that traditional ‘reprogramming’ of bat cells using Oct-4, Sox2, Klf4 and c-Myc (OSKM) does not result in pluripotency as it does in most cells. The specification states, “No ‘iPS-like’ cells are obtained from these primary cells under these conditions, iPS cells are easily obtained using this system in other species including in man” (page 26, lines 27-28). This supports that bat cell reprogramming is different from other mammals. OSKM expression resulted in “Only transient morphological changes…” (page 27, line 27). Thus, it is held that reprogramming changes observed using ECM in bat cells do not necessarily translate to other mammalian species.
To address this unpredictability, the specification does carry out ECM overexpression in fibroblasts of other mammalian species. Examples 2-4 reprogram bovine, human and horse fibroblasts, respectively. The examples prophetically teach that growth curves will be made to determine the long-term proliferation potential but the results are not presented. The ponly characteristics of the resulting ECM reprogrammed cells is “the appearance of major morphological changes in BEF…” (page 33, lines 3-4), “the appearance of major morphological changes in HEF…” (page 35, lines 11-12), and “the appearance of major morphological changes in HorseEF…” (page 38, lines 1-2).
Example 5 discusses the differentiation of stem cells into various lineages but only describes keratinocyte medium (to induce keratinocytes). The only result given is observation of morphological changes. There is no characterization of what cell type results from culture in keratinocyte media or that the ‘stem’ cells can differentiate into any specific differentiated cell type.
WO2018138091 teaches expression of CDX-2 and c-MYC in bovine cells (BCM) led to altered cell cycle profile that is typical of stem cells. No differentiation studies on these cells were carried out nor is the effects of ESRRB expression on the cells discussed. The art is otherwise silent with regard to the induced expression of the ECM combination on mammalian cells.
With regard to characteristics of stem cells, it was well-accepted in the art that stem cells have the ability to differentiate into a variety of cell types along with the capacity for self-renewal. Zakrzewski (Stem Cell Research & Therapy (2019) 10:68, 22 pages) taught, “Totipotent stem cells are able to divide and differentiate into cells of the whole organism…”, “Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta…”, “Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages…”, “Oligopotent stem cells can differentiate into several cell types…” and “Unipotent stem cells are characterized by the narrowest differentiation capabilities…” (page 1, right column). The differentiation capacity of mammalian cells expressing ECM is not taught by the specification or the art of record. Thus, there is no support that the cells obtained by the claimed can be differentiated or what they can differentiate into.
With regard to mammalian species of cells other than bat cells, the only effect of the claimed method is altered cell morphology and the characteristic changes observed are not described. There is no guidance with regard to levels of Henipaviral infectivity, which appears to be the object of the invention. Thus, given the guidance in the specification, the lack of guidance from the art at the time of filing and the unpredictability of applying cellular reprogramming to bat cell as supported by the specification, it would require undue experimentation to carry out the claimed method to obtain cells that possess all stem cell characteristics from any species of mammal including bat. It appears the specification supports reprogramming bat somatic cells to increase their replicative capacity and henipaviral infection capacity.
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 rejection of claims 1, 3-4, 7 and 16-17 under 35 U.S.C. 103 as being unpatentable over Mahapatra (Int. J. Dev. Biol. 61: 81-88) in view of Lluis (2009, Cell Cycle 8:8, 1138-1144), Mendlein et al (U.S. PGPUB 20120207744) and Woltjen et al (2009, Nature, 458(9): 766-771) is withdrawn in light of Applicant’s amendments and supporting remarks. The references relate to induction of pluripotency and individual replacement of factors. No reference teaches the effects of ESRRB, CSX-2 and c-Myc without the other well-known reprogramming transcription factors. The references merely teach a role for the three genes. The effects of this combination, alone, therefore, would have been unpredictable at filing.
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