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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, in the reply filed on 8-17-26 is acknowledged.
Claim 9 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 8-17-26.
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.
Written Description
Claims 1-8 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.
The specification lacks written description for making any motor neuron from any “urine-derived cell” using any “transcription factor for inducing differentiation into a motor neuron” as required in claim 1.
Pg 47, para 73, teaches: “In the following Examples, unless otherwise noted, used were 3 strains (3805-8505 derived from healthy individuals, and 3805-8506 and 3805-8507 derived from sporadic amyotrophic lateral sclerosis patients) obtained from REPROCELL Inc., Japan, and 5 strains derived from healthy individuals (UDC280, UDC283, UDC304, UDC305, and UDC306) obtained from Evercyte GmbH, Austria, as human urine-derived cells (UDCs)”; however, the specification fails to teach the structure or function of the cells. Therefore, the concept of UDCs lacks written description. The specification fails to correlate the isolated mammalian UDCs in para 73 or the isolated mammalian fibroblasts in the Examples (pg 49, para 79) to cells in vivo or to invertebrate, insect, fish, amphibian, reptile or bird cells as broadly encompassed by claim 1. At minimum the specification is limited to using isolated mammalian fibroblasts.
Pg 49, para 77, teaches transfecting isolated mammalian fibroblasts with a nucleic acid sequence encoding NGN2, Sox11, ISL1 and LHX3.
Pg 51, para 82, describes culturing the transfected fibroblasts in “neuro differentiation medium” on days 2-14 followed by “neurobasal medium”. The sentence bridging pg 52-53 does not make grammatical or scientific sense: “Co-culture with skeletal muscle cells were performed as follows: C2C12 cells that have been differentiated with 1% FBS or 2% horse serum and 1 µM insulin were detached by treatment with 0.05% trypsin-EDTA, and seeded on the motor neurons to culture for 7 days”. Therefore, the step after day 14 cannot be discerned. This step lacks written description and is essential to the invention because it is required to obtain motor neurons from the transfected cells.
The specification has written description for transfecting isolated mammalian fibroblasts with nucleic acid sequences encoding NGN2, Sox11, ISL1 and LHX3 followed by culture in “neurodifferentiation medium” on days 2-14 followed by “neurobasal medium” but does not provide adequate written description for using UDCs, using any “transcription factor for [differentiation into a] motor neuron”, or obtaining motor neurons.
The specification lacks written description for obtaining a cell that expresses ISL1, LHK3, HB9, ChAT, SMI32, or VAChT as required in claims 3-6 for reasons set forth above. The claims are also grammatically incorrect because “positive for (X) [or Y or I and II] at least one [sic]” does not make sense.
The specification does not correlate using NGN2, Sox11, ISL1 and LHX3 to using NGN2, ASCL1, BRN2, NEUROD1, or miR9/9*124, and ISL1, LHX3, or HB9 to make as required in claim 7 for making motor neurons for reasons set forth above.
The media components in claim 8 lack written description for reasons set forth above because there are two culture steps: culture in “neurodifferentiation medium” on days 2-14 followed by “neurobasal medium”. Each medium has multiple components that are essential to the invention, but are missing from the claim. Applicants fail to correlate those two media comprising multiple components to any one medium comprising FGF, forskonlin or dorsomorphin as required in claim 8.
Enablement
Claims 1-8 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 transfecting isolated mammalian fibroblasts with nucleic acid sequences encoding NGN2, Sox11, ISL1 and LHX3 followed by culture in “neurodifferentiation medium” on days 2-14 followed by “neurobasal medium”, does not reasonably provide enablement for using UDCs, using any “transcription factor for [differentiation into a] motor neuron”, or obtaining motor neurons. 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/use the invention commensurate in scope with these claims.
The specification does not enable making any motor neuron from any “urine-derived cell” using any “transcription factor for inducing differentiation into a motor neuron” as required in claim 1.
Pg 47, para 73, teaches: “In the following Examples, unless otherwise noted, used were 3 strains (3805-8505 derived from healthy individuals, and 3805-8506 and 3805-8507 derived from sporadic amyotrophic lateral sclerosis patients) obtained from REPROCELL Inc., Japan, and 5 strains derived from healthy individuals (UDC280, UDC283, UDC304, UDC305, and UDC306) obtained from Evercyte GmbH, Austria, as human urine-derived cells (UDCs)”; however, the specification fails to teach the structure or function of the cells. Therefore, the concept of UDCs is not enabled. The specification fails to correlate the isolated mammalian UDCs in para 73 or the isolated mammalian fibroblasts in the Examples (pg 49, para 79) to cells in vivo or to invertebrate, insect, fish, amphibian, reptile or bird cells as broadly encompassed by claim 1. At minimum the specification is limited to using isolated mammalian fibroblasts.
Pg 49, para 77, teaches transfecting isolated mammalian fibroblasts with a nucleic acid sequence encoding NGN2, Sox11, ISL1 and LHX3.
Pg 51, para 82, describes culturing the transfected fibroblasts in “neuro differentiation medium” on days 2-14 followed by “neurobasal medium”. The sentence bridging pg 52-53 does not make grammatical or scientific sense: “Co-culture with skeletal muscle cells were performed as follows: C2C12 cells that have been differentiated with 1% FBS or 2% horse serum and 1 µM insulin were detached by treatment with 0.05% trypsin-EDTA, and seeded on the motor neurons to culture for 7 days”. Therefore, the step after day 14 cannot be discerned. This step is not enabled because it is essential to obtain motor neurons from the transfected cells.
The specification is enabled for transfecting isolated mammalian fibroblasts with nucleic acid sequences encoding NGN2, Sox11, ISL1 and LHX3 followed by culture in “neurodifferentiation medium” on days 2-14 followed by “neurobasal medium” but does not enable using UDCs, using any “transcription factor for [differentiation into a] motor neuron”, or obtaining motor neurons.
The specification does not enable obtaining a cell that expresses ISL1, LHK3, HB9, ChAT, SMI32, or VAChT as required in claims 3-6 for reasons set forth above. The claims are also grammatically incorrect because “positive for (X) [or Y or I and II] at least one [sic]” does not make sense.
The specification does not correlate using NGN2, Sox11, ISL1 and LHX3 to using NGN2, ASCL1, BRN2, NEUROD1, or miR9/9*124, and ISL1, LHX3, or HB9 to make as required in claim 7 for making motor neurons for reasons set forth above.
The media components in claim 8 are not enabled for reasons set forth above because there are two culture steps: culture in “neurodifferentiation medium” on days 2-14 followed by “neurobasal medium”. Each medium has multiple components that are essential to the invention, but are missing from the claim. Applicants fail to correlate those two media comprising multiple components to any one medium comprising FGF, forskonlin or dorsomorphin as required in claim 8.
Indefiniteness
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 1-8 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.
The metes and bounds of UDCs in claim 1 cannot be determined. Pg 47, para 73, teaches: “In the following Examples, unless otherwise noted, used were 3 strains (3805-8505 derived from healthy individuals, and 3805-8506 and 3805-8507 derived from sporadic amyotrophic lateral sclerosis patients) obtained from REPROCELL Inc., Japan, and 5 strains derived from healthy individuals (UDC280, UDC283, UDC304, UDC305, and UDC306) obtained from Evercyte GmbH, Austria, as human urine-derived cells (UDCs)”; however, the specification fails to teach the structure or function of the cells. Therefore, the concept of UDCs is indefinite.
The metes and bounds of “transcription factor for [differentiation into a] motor neuron” in claim 1 cannot be determined. While NGN2, ASCL1, BRN2, NEUROD1, or miR9/9*124, and ISL1, LHX3, or HB9 appear to be encompassed by the phrase, the specification and the art at the time of filing do not define the phrase. Therefore, the concept is indefinite.
The phraseology in claims 3-5 is indefinite because it has grammatic errors and fails to clearly set forth the structure of the cells obtained. The phrase “positive for (X) [or Y or I and II] at least one [sic]” does not make sense. They are also unclear because they do not clearly refer to the motor neuron obtained at the end of claim 1.
The phrase “to obtain a cell positive for at least SMI32” in claim 6 is indefinite because it does not clearly refer to the motor neuron obtained at the end of claim 1 or clearly set forth that the motor neuron obtained expresses SMI32.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3-8 are rejected under 35 U.S.C. 102a1 as being anticipated by Liu (Cell Rep. 2016, Vol. 14, pg 115-128).
Liu transfected isolated mammalian fibroblasts with a nucleic acid sequence encoding NGN2, Sox11, ISL1, and LHX3 and culturing them in medium containing FGF2, forskolin and dorsomorphin such that motor neurons were obtained (pg 116, 1st col. lines 6-30; pg 125, 2nd col., 4 lines from the bottom to pg 126, col. 1, line 36). The fibroblasts of Liu are UDCs as required in claim 1 because fibroblasts are found in the urine.
The motor neurons expressed HB9, HB9, and VAChT as required in claim 3-5 (pg 116, col. 2, last para).
The cells expressed ISL1 as required in claim 5 because they were transfected with a vector encoding ISL1 and LHX3.
The motor neurons inherently MUST express SMI32 as required in claims 3-6 because they are motor neurons.
The cells were transfected with NGN2, Sox11, ISL1, and LHX3 as required in claim 7 (pg 125, last 3 lines).
The medium contained FGF, forskolin, and dorsomorphin as required in claim 8 (pg 116, col. 1, 1st full para).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5, 7, 8 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (Cell Rep. 2016, Vol. 14, pg 115-128) in view of Meng (“Induction of fibroblasts to neurons through adenoviral gene delivery”, Cell Res., 2011, Vol. 22, pg 436-440).
Liu transfected isolated mammalian fibroblasts with a nucleic acid sequence encoding NGN2, Sox11, ISL1, and LHX3 and culturing them in medium containing FGF2, forskolin and dorsomorphin such that motor neurons were obtained (pg 116, 1st col. lines 6-30; pg 125, 2nd col., 4 lines from the bottom to pg 126, col. 1, line 36). The fibroblasts of Liu are UDCs as required in claim 1 because fibroblasts are found in the urine.
Liu did not teach introducing the nucleic acids via adenoviral vectors as required in claim 2.
However, doing so was well-known as described by Meng (title, throughout).
Thus, it would have been obvious to those of ordinary skill in the art at the time of filing to reprogram fibroblasts into neurons as described by Liu using adenoviral vectors as described by Meng. Those of ordinary skill in the art at the time of filing would have been motivated to avoid lentiviral vectors that integrate into the genome as described by Meng (pg 439, col. 1, 2nd full para).
Thus, Applicants' claimed invention as a whole is prima facie obvious in the absence of evidence to the contrary.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Xu (Cell Biosci., 2020, Vol. 10, No. 116, pg 1-25) reprogrammed human fibroblasts into neurons (title; pg 5, Table 1, “Motor Neurons”).
Perez-Siles (Sci. Reports, 2020, Vol. 10, No. 9262, pg 1-13) differentiated iPS cells into motor neurons.
Son (Cell Stem Cell, 2011, Vol. 9, pg 205-218) converted mouse fibroblasts into motor neurons using nucleic acids encoding (pg 215-216).
Vierbuchen (“Direct conversion of fibroblasts to functional neurons by defined factors”, Nature, 2010, Vol. 463, pg 1035–1041).
Nagai (Sci. Reports, 2024, Vol. 14, No. 27011, pg 1-9) is applicants’ own work.
Sato (Frontiers in Med., 2019, Vol. 12, pg 1-9) taught stem cells in urine.
No claim is allowed.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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