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 .
Applicant’s reply dated 07/09/2026 has been received.
Claims 1,4,7, and 16-17 are under consideration.
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.
Claim 1,4,7, and 16-17 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.
Claim 1 is unclear because the newly added limitations use relative terminology and do not provide a baseline “altered morphology” and “increased susceptibility”. The phrase “more than twice faster as their original somatic cells” is unclear. It is not clear if the comparison is to proliferation rate prior to reprogramming or if the comparison is intended to be reprogrammed cells compared to un-reprogrammed counterparts. Clams 4,7, and 16-17 are unclear based on their dependency from claim 1.
Claim 4 was previously objected to but, as amended, is now unclear. It is not clear if the phrase “primary cells of” modifies each tissue in the recited list of tissues. Previously, it appeared it did. However, it would read “primary cells of…adipose cells”. Particularly, inclusion of “and parenchymal tissues containing primary fibroblasts…or skeletal tissues” inserted in the list of tissues was misleading. Use of an “and” and an “or” in the list is confusing.
Claim 4 is interpreted as the somatic cells being primary cells obtained from a tissue selected from blood, adipose, skin, hair, skin appendages, internal organs, mesenchyme and parenchyma.
The phrase “parenchymal cells containing fibroblasts” is unclear because a cell does not contain a cell.
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 1,4,7, and 16-17 remain 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 relative to the starting cells, have increased doubling capacity and are more susceptible to Henipavirus infection,
and for
an in vitro method of reprogramming human and bovine fibroblasts using the claimed method steps wherein the cells take on an altered morphology relative to the starting fibroblast,
and for
an in vitro method of reprogramming equine fibroblasts using the claimed method steps wherein the cells take on an altered morphology and increased doubling capacity relative to the starting fibroblasts
does not reasonably provide enablement for reprogramming any species of cells into stem cells exhibiting any altered morphology, rapid proliferation of any species other than bat, or increased susceptibility of any species other than bat and bovine when the virus is a henipavirus or loss of any characteristic of the somatic 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 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).
Applicant’s amendments to the claims, Remarks and the Pain Declaration dated 07/27/2026 have been considered and are partially persuasive. It is appreciated that Applicant has added stem cell characteristic limitations to the claims and showed some data supporting certain (but not all claimed) stem cell characteristics for species of cells other than bat and for non-bat cells other than fibroblasts. For this reason, a new, enabled breadth is set forth above because newly presented data has supported some, but not all, of the breadth of functional effects added to the claims for each recited species. Applicant is also requested to consider whether “rapid proliferation” is an accurate reflection of the observed differences in cell division. Reprogrammed cells appear to have about the same growth curve up until the primary cell curve levels out as the cells stop dividing. It appears “increased doubling capacity” would be more reflective of the data shown in Figure 2. Additionally, recitation of “lost characteristics” is overly broad and encompasses loss of characteristics that the data of record does not support.
As set forth below, reprogramming differentiated cells with the well-known OSKM factors that work in numerous mammalian species, does not work the same in bats. The Specification states at page 26, “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.” For this reason, data supporting stem cell characteristics brought about by the claimed ECM conditions with bat cells are not readily extrapolated to other mammalian species.
The claims now require increased susceptibility to virus infection. The Specification at pages 29-30 discusses NiV infection of pig, cow and bat cells. However, porcine cells were reprogrammed with OSKM, not ECM. The specification only specifies reprogramming of bovine cells of unknown cell type and bat tracheal cells with ECM and showed increased NiV infectivity in each of these two species. No other virus is shown to have increased infectivity nor is Nipah virus shown to have increased infectivity of ECM-reprogrammed cells other than bat and bovine cells of unknown starting cell type. Wu (2018, Cell 172, 423–438) taught stem cells are highly resistant to viral infection. Thus, it is not clear if the increased infectivity is specific to the method of reprogramming and the reprogrammed differentiation state, the species of mammal or the virus type itself. Furthermore, with regard to the starting cell type, other than bat tracheal cells, it appears other mammalian cell types used were all fibroblasts. Fibroblasts were known at the time of filing, to be more plastic and not carry over terminally differentiated cell type signatures and phenotypes when reprogrammed. Chin (2014, Frontiers in Cell and Developmental Biology, Vol. 2, 46, doi: 10.3389/fcell.2014.00046) taught, for example, that forced expression of MyoD cold activate muscle specific genes but could not suppress the starting cell phenotype. Thus, it is held to be unpredictable what effects forced expression of ECM would have in various terminally differentiated cell types other than the more plastic, less differentiated fibroblasts.
In sum, with regard to reprogramming with ECM, what Applicant has support for in the Specification and the Declaration is the claimed “altered morphology” of reprogrammed fibroblasts for bovine, human, and equine, relative to the starting fibroblastic morphology. Full breadth of bat cell type is found enabled as the bat tracheal cells are fully differentiated. Applicant has supported the recited rapid proliferation phenotype for horse fibroblast (Declaration), increased doubling capacity and increased NiV infection for bat (Specification). With regard to bovine and susceptibility to viral infection, the Specification does not appear to disclose the starting cell type.
Rejection of record
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.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632
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