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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/6/25 has been entered.
Claim 48 is canceled.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 21-22 in the reply filed on 09/09/2024 is acknowledged.
Claims 45-47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/09/2024.
Claims 21-28, 32-34 and 41 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.
The rejection of claims 21-28,30-34,41 and 48 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn as the claims are no longer drawn to cell regeneration. The denial to priority to this subject matter is also withdrawn.
Claims 21-28,30-34,41 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 21 is unclear because it is drawn to a method for regenerating tissue but ends with a cell that is capable of regenerating tissue. Thus, the method does not end with a regenerated tissue but ends with what appears to be a reprogrammed cell within a tissue. Claims 22-28,30-34,41 depend from claim 21.
Claim Rejections - 35 USC § 112a
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 21-28,30-34 and 41 remain rejected and newly added claim 48 is 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 is withdrawn. It appears to be Applicant’s argument that if a cell is assayed at 4 days or 7 days, expression of the iTR is stopped because the cell is being assayed. Claim 27 now ends with the cell being capable of regenerating the tissue. With this new limitation, the claim is no longer drawn to administering the iTRs for 4 or 7 days, resulting in tissue regeneration.
Claims 21-28,30-34 and 41 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
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.
The claims are now drawn to a method of regenerating tissue that ends with a cell capable of regenerating tissue. The nature of the invention relates to an ex vivo method of regenerating cells by administration of reprogramming factors Oct4 Sox2, Klf4, NANOG, ESRRB, CEBPA, MYC, TERT, LIN28A and/or LIN28B, alone or in combinations, to cells, ex vivo, without reversion of cells to pluripotency.
The specification fails to support this ex vivo method of cell regeneration. The specification teaches gene ecpression analyses to identifu gene excpression patterns that are associated with an embryonic state or with the fetal/adult state. It then teaches use of these characteristic markers to screen for factors or agents that can transition cells to the embryonic phase. Example 1 teaches increased
The specification does not teach what is regenerated or what is encompassed by “regenerating one or more adult cells”. The phrase implies the cells are dead in order for them to regenerate. The specification teaches gene expression analyses to identify gene expression patterns that are associated with an embryonic state or with the fetal/adult state. It then teaches use of these characteristic markers to screen for factors or agents that can transition cells to the embryonic phase. Example 1 teaches increase COX7A1, NAALADL1, and PLPP7 as genes more highly expressed following embryonic-fetal transition (EFT) with their upregulation coinciding with EFT. Example 5 teaches screening for factors that lead to reduced COX7A1 in various cancer cell lines. In Example 7, an in vitro method is used to get cells from and in vitro cell line to a pre-fetal stage using Oct4, Sox2, Klf4, Myc and Lin28a (OSKML). It was found that Lin28A overexpression correlated with decreased COX7A1 as well as other indicators of embryonic state. In Example 9, a COX7A1 knockout mouse was shown to heal faster in an ear punch wound model. Example 11 teaches addition of GFER, AMH and valproic acid to a fibroblast monolayer in culture. A scratch was made in the monolayer and the added components were found to lead to faster coverage of the wounded zone compared to culture without the added components. Example 12 teaches that huVEC derived exosomes can turn on fetal/adult markers in embryonic endothelial cells when they fuse. Example 9 is an in vivo method where the COX7A1 knockout mouse showed accelerated wound healing. This in vivo model, along with the in vitro experiments, fail to support a method of regenerating tissue by delivering the iTR factors to cells of a tissue ex vivo. While delivery of OSKML is supported by the specification to decrease COX7A1 expression and COX7A1 null mice are found to undergo more rapid wound healing, this fails to support that delivery of OSKML or other recited combination of iTRs, will lead to treatment of ocular disease or disorder.
The art prior to and post-filing held that in vivo delivery of reprogramming factors (OSKML) resulted in some cells becoming pluripotent and forming teratomas throughout the body. Delivery of these factors to cells in vitro or exvivo leads cells to reprogram to pluripotency over time. While intermediates in reprogramming exist, there is nothing on the record to show how to control the expression of the reprogramming factors to avoid pluripotency. Chiche (2017, Cell Stem Cell, 20:407-414) taught that age affects reprogramming. Teratomas formed more often in older mice when OSKM was introduced, indicating a complex nature and need for control of expression levels in vivo (page 411, left). Prior to filing, Abad (2013, Nature, 502:340-345; IDS) taught that OSKM led to formation of teratomas, in vivo.
Claim 21 requires that no pluripotent cells be made by introduction of nucleic acids encoding the recited iTRs. However, the specification fails to teach how to administer the reprogramming factors ex vivo, such that reversion to pluripotent cells does not occur. The claims are quite broad and encompass many combinations of factors know to lead to pluripotency. The specification does not teach how to stop expression of those factors to lead to cells that are not pluripotent but have the now claimed expression characteristics. It appears Applicant may be claiming cells at 2 specific points along a temporal time line of re-, de-, or trans-differentiation’.
The claims encompass administering OSKM to cells of a tissue ex vivo and in vivo, which is supported by the art to lead to pluripotency. In vitro reprogramming to pluripotency with OSKM can take 25 days (see Takahashi, 2007, Cell, 131:861-872, IDS, specifically page 862, right column). Thus, administering these factors for less than 25 days will lead to cells that are in the process of reverting to pluripotency. However, there is nothing of record to indicate that these cells regenerate. Moving towards an embryonic state of gene transcription does not support that the cells are regenerated. The specification does not define cell regeneration.
Furthermore, the claims recite a list of factors, some of which are supported to reprogram cells to pluripotency when used in various combinations. The specification does not show a single factor or set of factors that leads to regeneration.
Therefore, in light of the breadth of the claims, the lack of guidance in the specification with regard to in vivo introduction of one or more of Oct4 Sox2, Klf4 and Myc, Nanog, ESRRB, NR5A2, CEBPA, MYC, TERT, LIN28Aa and LIN28B and the guidance in the art with the differential effects of the factors in vivo vs. in vitro, as well as the inability to prevent cells from reaching pluripotency and forming teratomas, it would require undue experimentation to carry out the invention as claimed.
Applicant refers to the optimized protocol in Example 7. Example 7 refers to numerous genes and small molecules that can be combined in “diverse combinations” for differing periods of time. Applicant argues the opposite, stating that the combinations are limited. The combinations are limited in that they are not infinite. But the Specification also contemplates combinations of numerous small molecule reprogramming agents. The claims require the resulting cell types do not express HELLS and/or DNMT3B and has decreased COX7A1 expression. The claims also recite that the iTR factors are expressed for 4 days or 7 days. Example 7 only teaches expression of LIN28A leads to reduced COX7A1 and lack of HELLS and DNMT3B but it does not support that the factors were expressed for 4 days or for 7 days and it does not teach how to stop expression so that the cells do not continue towards pluripotency. Pulling cells out of the tissue to assay gene expression may stop iTR expression at 4 or 7 days but then that cell is no longer part of the method of regenerating tissue. The nexus between expression of iTRs for 4 or 7 days and regenerated tissue has not been made. THe specification hasn’t taught how to stop iTR expression from mRNAs (now recited in claim 21) at 4 days or at 7 days or that doing so leads to tissue regeneration. THe specification merely supports that COX7A1 expression is decreased at day 4 and at day 7 of iTR expression. Applicant argues the specification contemplates that the method leads to dunction tissue regeneration. This is not supported.
Applicant argues that one of skill in the art would recognize that recitation of “tissue” would include the cells that make up the tissue. This argument is not persuasive as it relates to the claims. Tissue regeneration and cellular regeneration are not the same. Regeneration of a cell would be interpreted to leading a cell from senescing to one with restored function. Regeneration of a tissue is a restructuring process or a process where new cells are generated into the structure.
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 on M-F 6AM-2:30PM.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632